bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of diazepam from a controlled release capsule in healthy elderly volunteers
Authors: Wills Robert J.
Published: October 2006

A single dose open labelled two‐way randomized crossover study was used to assess the pharmacokinetics of diazepam from a controlled release capsule relative to standard release tablets in elderly volunteers. Eighteen volunteers received a single 15 mg controlled release capsule or a 5 mg tablet t.i.d. on one day. Diazepam plasma concentrations were determined at specific times over a 96‐h interval by an electron capture‐gas chromatographic method. Mean plateau plasma concentrations endured from 2 to 24h avoiding the peak to trough fluctuations associated with conventional t.i.d. dosing. Similar areas under the plasma concentration–time curve (AUC) values indicated equal extent of absorption between formulations and regimens. Comparing parameters in this same elderly population to a young adult population, previously administered the controlled release capsule, shows lower maximum concentrations and a longer plateau duration in the elderly volunteers. Although there is a twofold increase in the mean diazepam half‐life in the elderly when compared to young adults, the estimated apparent volume of distribution increased proportionately with half‐life to maintain a constant clearance. Thus, the total body clearance of diazepam appears to be age independent. The age‐dependent pharmacokinetics observed in this study are consistent with previously reported data involving diazepam. Overall, the controlled release capsule administered once daily mimics a t.i.d. regimen in elderly volunteeres.
Pharmacokinetics of repeated single oral doses of enalapril maleate (mk‐421) in normal volunteers
Authors: Till Alice E. , Gomez Hector J. , Hichens Martin , Bolognese James A. , McNabb W. R. , Brooks B. A. , Noormohamed F. , Lant A. F.
Published: October 2006

Enalapril, the ethyl ester of a potent angiotensin converting enzyme inhibitor, enalaprilat, was administered to healthy volunteers as a capsule containing 10 mg of the maleate salt, every 24 h for eight doses. Serum profiles show little accumulation of enalaprilat following eight daily doses of enalapril maleate. An average effective half‐life for accumulation of approximately 11 h was calculated from urine data. Comparison of observed 24‐h urinary recoveries of enalaprilat to predicted steady‐state recovery indicates that an ‘average’ steady state for enalaprilat is attained by the third or fourth dose of enalapril maleate. Statistical comparison of daily urinary recoveries, as well as Cmin values for enalaprilat, confirm this. Observed fluctuations in serum and urine data during apparent steady state suggest some day‐to‐day variability in the absorption of enalapril maleate and/or its hydrolysis to enalaprilat. An accumulation ratio of 1·3 for enalaprilat was calculated from the predicted steady‐state urinary recovery and observed urinary recovery for dose one.
Microcalorimetric investigations of drug–albumin interactions
Authors: Hardee G. H. , Fleitman J. S. , Otagiri M. , Perrin J. H.
Published: October 2006

Flow microcalorimetry was used to estimate primary binding constants for drug–albumin interactions. Measurements of heat of reaction at two temperatures illustrated the danger of extrapolation for pharmacokinetic purposes of measurements made at temperatures other than 37°. The method could be used to predict competition between two drugs for a single binding site. Major advantages over spectroscopic techniques included direct determinations of thermodynamic parameters, and the use of physiological concentrations of albumin.
Pharmacokinetic–pharmacodynamic modelling and simulation using the electrical circuit simulation program spice2
Authors: Thakker Kamlesh M.
Published: October 2006

The use of the electrical circuit simulation program SPICE2 for performing digital computer simulations of linear and non‐linear pharmacokinetic–pharmacodynamic models is described. SPICE2 utilizes the principles of network thermodynamics (thermodynamics of electrical circuits). These principles dictate analogy between the conservation laws of chemical reactions and mass transport and Kirchhoff's laws of current and voltage balance, and also prove that Fick's law of diffusion is isomorphous with the conductance form of Ohm's law. Detailed descriptions of program inputs, formats, and options for simulation of linear and non‐linear pharmacokinetic–pharmacodynamic systems are provided, with appropriate examples. Single as well as multiple dose simulations (accumulation kinetics and dynamics) are discussed. The advantages of SPICE2 over other available simulation packages, including user‐friendliness, ease of operation, versatility, power, and the economy of time and effort afforded, are emphasized. The educational value of SPICE2 as a highly versatile tool for teaching both fundamental and complex pharmacokinetic–pharmacodynamic concepts, as well as its routine usage in elucidating complex research problems, are also discussed.
In vitro and in vivo bioequivalence of commerical prednisone tablets
Authors: Francisco G. E. , Honigberg I. L. , Stewart J. T. , Kotzan J. A. , Brown W. J. , Schary W. L. , Pelsor F. R. , Shah V. P.
Published: October 2006

The purpose of the study was to examine the bioequivalence of five commerically available oral prednisone products. The in vivo study utilized 18 healthy males, each of whom was administered 20 mg of prednisone as a reference solution or as a tablet in a 6‐week, six‐way crossover design. Blood was collected and serum was assayed, using an HPLC procedure specific for prednisone and prednisolone. Mean pharmacokinetic parameters (t1/2, ke, Cmax, and AUC) were determined. ANOVA was performed on the prednisone and prednisolone data (F‐test, p < 0·05) as well as Duncan's multiple range analysis. Dissolution tests were also performed on each of the five products in order to test the relationship between dissolution and bioequivalence among prednisone products. The in vitro study consisted of a standard USP dissolution test which included tablets from the same lots as the tablets used in the in vivo study. The data showed no statistical difference in any of the pharmacokinetic parameters among tableted products, subjects, or dosing periods in the study. There was also no statistical difference in the dissolution study among the five commerical tablet forms.
Theophylline disposition in residents living near a chemical waste site
Authors: Cuddy Mary Linda Stotter , Gardner Mark J. , Mangione Antoinette , Yurchak Anthony M. , Paigen Beverly , Jusko William J.
Published: October 2006

The pharmacokinetics of theophylline were compared in 11 residents living near a chemical waste site (Love Canal) and 25 control subjects from Western New York. Love Canal residents had documented chronic exposure to a variety of organic and halogenated compounds. Only young adults with no overt diseases were examined. Theophylline plasma clearances were similar in the two groups, although the enzyme inductive effects of tobacco smoking were further confirmed. The lack of environmental effect on theophylline clearance indicates that no chronic net change in one pathway of microsomal P‐448 oxidation occurred. The possibility of acute changes related to seasonal chemical exposure and mixed inductive/repressive effects from the myraid types of chemicals may confound the data.
Distribution of sodium valproate and gaba metabolism in cns of the rat
Authors: Hariton Claude , Ciesielski Lucien , Simler Simone , Valli Marc , Jadot Guy , Gobaille Serge , Mesdjian Edouard , Mandel Paul
Published: October 2006

The distribution of VPA has been investigated in several brain areas of the rat, and GABA increases were measured. A biphasic exponential decay was observed for VPA; the slowest decrease was noted in the olfactory bulbs and in the hypothalamus where GAD and GABA‐T activities were the highest. The data may be correlated with the prolonged effect of VPA in these areas.
Bioavailability studies with ciglitazone in beagles II. Effect of propantheline bromide and metoclopramide HCL on bioavailability of a tablet
Authors: Cox Steven R. , Harrington Ellen L. , Capponi Vincent J.
Published: October 2006

Bioavailability studies in fasted dogs with ciglitazone (CGZ), an oral hypoglycemic agent, suggested that an absorption window could contribute to the poor oral availability of CGZ. If so, propantheline bromide (PPB) could increase the residence time of CGZ at absorption sites and increase its bioavailability. Using this rationale, a Latin square study was conducted with CGZ in fasted dogs (n = 10) using treatments of a single 125mg tablet with and without 1.2 mg kg−1 i.m. PPB. PPB was given in a single dose 1 h prior to administration of CGZ. Plasma concentrations of CGZ were assayed by HPLC. PPB significantly increased the AUC of CGZ by a ratio of 1.2 : 1 (p < 0.01). PPB also increased Tmax from 2–8 h (p<0.001), and appeared to produce first order absorption of CGZ.

In a separate CGZ study using fasted dogs (n = 10), a single 125mg tablet was administered with and without i.v. metoclopramide HCI (MCP). A 10mg dose of MCP was given 15 min prior to dosing with CGZ and repeated 1 h after dosing. MCP increases GI motility and was expected to decrease residence time of CGZ. MCP had no effect on Tmax, but significantly decreased AUC by 8 per cent (p = 0.05). MCP also reduced Cmax by 16 per cent (p = 0.06). Taken as a whole, these data suggest that the effect of meals to increase bioavailability of CGZ could be mediated at least in part, through an increase in GI residence time.
A method for determining the pharmacokinetics of endogenous creatinine without exogenous creatinine administration
Authors: Chow M. S. S.
Published: October 2006

A method for determining the individual pharmacokinetics of endogenous creatinine is derived and applied in 10 post‐renal transplant patients. All patients had rapidly decreasing serum creatinine concentrations (C), but relatively constant creatinine clearance (Clcr) during the study period. Based on the multiple consecutive Clcr and the corresponding C, the elimination rate constant (K), volume of distribution (V), and daily creatinine production rate (R) for each patient were derived. The creatinine ‘normal’ t1/2 (corresponding to a Clcr of 120 ml min−1) was also calculated. In the 10 patients studied, the observed Clcr ranged from 29.5 to 72.7 ml min−1. The corresponding calculated mean K was 0.076 ± 0.028 h−1; R was 20.0 ± 5.7 mg kg−1 day−1, and V was 0.60 ± 0.1 l kg−1. The ‘normal’ t1/2 was 4.0 ± 0.93 h. These pharmacokinetic parameters are consistent with those derived from radiotracer studies and other methods reported in the literature. The present study shows that the individual endogenous creatinine pharmacokinetics can be determined by a relatively simple and noninvasive method in certain selected patients if the appropriate serum and urinary creatinine concentrations are obtained.
First‐pass elimination of lidocaine in the rabbit after peroral and rectal route of administration
Authors: Ritschel W. A. , Elconin H. , Alcorn G. J. , Denson D. D.
Published: October 2006

Lidocaine shows pronounced first‐pass metabolism upon peroral administration in man (about 30 per cent peroral bioavailability). Since the rectal bioavailability is about 65 per cent in man it is assumed that some drug is directly absorbed into systemic circulation by‐passing the liver. In rats peroral bioavailability is about 8 per cent whereas rectal bioavailability is about 100 per cent. This indicates that the rat is not a suitable model to study rectal lidocaine dosage forms. The purpose of this study was to investigate lidocaine disposition and bioavailability in rabbits after peroral and rectal administration. The peroral bioavailability in rabbits was found to be about 6 per cent and the rectal bioavailability is about 33 per cent. The results indicate that the rabbit is a suitable model for the study of systemic absorption of rectal lidocaine dosage forms.
Electron‐capture gas chromatographic determination of loprazolam in plasma and a pharmacokinetic application
Authors: Levasseur F. A. , Caillé G. , Elie R. , Vézina M. , Larivière L.
Published: October 2006

A sensitive and specific gas chromatographic method, using an electron capture detector, for the measurement of plasma concentrations of loprazolam (HR‐158) is described. Retention times of the hydrolysis product of loprazolam (2‐amino‐2′‐chloro‐5‐nitrobenzophenone) and of the internal standard (2‐amino‐2′‐ fluorobenzophenone) were, respectively, 9 and 7 minutes. The sensitivity of the assay was 1.0 ng ml−1 of plasma, and for drug concentrations ranging from 1.0 to 15 ng ml−1 the mean recovery from plasma was 94.4 per cent and the mean coefficient of variation 9.8 per cent. This method was used to determine some pharmacokinetic parameters of loprazolam after administration of 2 × 1 mg capsule doses to nine healthy. fasted volunteers. The mean t1/2 was 6.4 h. mean AUCx 65.42 ng.h ml−1, and the mean clearance 0.51 l min−1.
Effect of time of dosing on the disposition of oral cibenzoline
Authors: Brazzell R. K. , Khoo K.‐C. , Schneck D. W.
Published: October 2006

Single oral doses of cibenzoline were administered to eight healthy volunteers on two different occasions, once at 8.00 am and once at 10.00 pm, in a randomized crossover design with at least one week separating treatments. A fast was maintained for 12 hours prior to and for 2 hours after the morning dose and the subjects did not lie down for at least 12 hours after dosing. A standard dinner was eaten 3 hours prior to the evening dose, and a fast was maintained for 10 hours after dosing; the subjects laid down 2 hours after dosing for at least 6 hours. Blood was collected at specific times for 72 hours and the total volume of urine voided was collected through 72 hours. Cibenzoline concentrations in plasma and urine were measured by HPLC. Cibenzoline absorption was slower in 7 of the 8 volunteers following the evening dose relative to the morning dose. Mean ± S.D. tmax for the evening dose was 2.6 ± 0.5 hours compared to 1.7 ± 0.8 for the morning dose. The corresponding mean ± S.D. Cmax following the morning dose was 446 ± 124 ng ml−1 compared to 402 ± 114 ng ml−1 after the evening dose. The mean ± S.D. AUC was 3328 ± 1101 ng.h.ml−1 after the morning dose and 3561 ± 1430 ng.h.ml−1 after the evening dose. The harmonic mean half‐life was 7.4 hours after both treatments. These data indicated that the total amount of drug absorbed and the elimination rate constant of the drug had not varied between treatments. Plasma concentrations 12 hours after the evening dose were statistically higher than those after the morning dose. The observation was consistent with the statistically higher morning trough concentrations that had been observed previously during a 12‐hour chronic dosing. There was no evidence of diurnal variation in the renal excretion of cibenzoline and the elimination half‐life and total amount of drug recovered in the urine were similar for the two times of administration. It appeared that the only pharmacokinetic difference following the morning or evening dosing was the slightly slower absorption rate at night, which should be of no clinical significance.
The disposition of the local anaesthetic, pentacaine, in rats and mice
Authors: Bezek Š. , Ščasnár V. , Trnovec T. , Ďurišová M. , Faberová V. , Beneš L.
Published: October 2006

The pharmacokinetics of pentacaine, a new local anaesthetic agent from the group of carbanilates, was investigated in the rat at a dose of 2 mg kg−1 i.v. and per os. A three‐compartment open model gave the best fit to the data. The model parameters are: t1/2 99.0 ± 14.1 min, Vss 7411.1 ml kg−1, Cl 77.9 ml min−1 kg−1; after oral administration t1/2 ab 4.9 ± 1.9 min, bioavailability 59.1 per cent, and extent of absorption 79.3 per cent. Pentacaine is eliminated almost entirely by metabolism. The metabolites are excreted equally in the urine and faeces at a relatively slow rate. The pharmacokinetics of pentacaine was linear in the dose range 0.008–4 mg kg−1. The whole‐body autoradiography in mice showed rapid transfer of 3H radioactivity from the vessels to tissues and a markedly heterogenous disposition pattern in organs.
A pharmacokinetic approach to the establishment of biopharmaceutic characteristics of different acetylsalicylic acid formulations in man
Authors: Raghoebar Maikel , Vrancx Fanny , Van Ginneken Cees A. M.
Published: October 2006

Eleven acetylsalicylic acid (ASA) formulations were administered to 26 healthy volunteers in a cross‐over design. The properties of the preparations differed from conventional, effervescent, buffered to buccal. The objectives of this study were:

Consideration of the general aspects of a biopharmaceutical study: which parameter for which biopharmaceutic characteristic?

Measurement of the kinetic parameters of ASA: first‐pass effect, mean residence time, mean appearance time, total body clearance, apparent volume of distribution, half‐lives, etc.

Comparison of the formulations.

Most of the formulations yield mean residence times for ASA of 0.3–1.0h, which do not differ significantly (p > 0.05). For most of the products the first‐pass effect is about 40 per cent; the average values of the apparent volume of distribution and whole body clearance, corrected for the first‐pass effect, are about 201 and 650 ml min−1, respectively. Peak levels are reached slowly for the buccal formulations, and rapidly for the buffered products. It is difficult, especially for ASA, to characterize the gastro‐intestinal absorption with pharmacokinetic model parameters, because the first‐pass effect is large and often elimination of ASA is faster than absorption. The model‐independent approach has the special advantages of calculating reliable pharmacokinetic parameters, and creating theoretical possibilities to characterize the absorption patterns of the different formulations in a quantitative way.

No significant differences in the values of the parameters are found between most of the formulations. The ASA first‐pass effect is reasonably constant and buccal application has no advantage. Enteric coating of the outer layer of ASA formulations causes inconsistent absorption and may be categorized under ‘artificial mistakes’.
Characterization of two metabolites of prethcamide by gas chromatography and mass spectrometry
Authors: Delbeke F. T. , Debackere M. , Jonckheere J. A. A. , De Leenheer A. P.
Published: October 2006

Crotethamide and cropropamide, both components of the respiratory stimulant prethcamide, are metabolized in humans by demethylation of the [(dimethylamino)‐carbonyl]‐propyl moiety. The resulting metabolites are characterized by gas chromatography–mass spectrometry of urinary extracts. The use of HCl to prevent losses by volatilization during the evaporation step, combined with methanol as solvent, complicates gas liquid chromatographic analysis of prethcamide. The resulting artifacts are identified.
Improving the ocular absorption of phenylephrine
Authors: Chien D. S. , Schoenwald R. D.
Published: October 2006

An oxazolidine prodrug of phenylephrine and the base form of phenylephrine were synthesized, suspended in sesame oil, and tested for mydriatic activity against phenylephrine HCL. The HCL salt was formulated as a viscous aqueous solution and as a sesame oil suspension. A dosing volume of 10 μl was instilled into rabbit eyes and the pupillary diameter was measured over time. A 0.045 M prodrug suspension was judged equal in mydriatic activity to a 0.45 M viscous solution of phenylephrine HCl with the exception that the time of maximum response occurred 60 min earlier with the prodrug.

When phenylephrine base was suspended in sesame oil at 0.045, 0.12, and 0.45M, the mydriatic activity was also greater than equimolar suspensions of phenylephrine HCl. The pH of tear fluids was also measured over time and found to rise 1·1, 0·70, and 0.30pH units for 0.45, 0.12, and 0.045 M suspensions of the base form but remain unchanged when phenylephrine HCl was instilled in the rabbit eye. The greater activity associated with the base form of phenylephrine was judged a result of the change in pH to favour the absorption of phenylephrine. This latter approach should be applicable to either weak acids or weak bases with pKa values outside of the normal pH range (7–8) of the tears and in concentrations greater than 0.045 M suspended in a non‐aqueous vehicle.
Absorption of iothalamate after oral administration and absorption enhancement by amino acids in dogs and rats
Authors: Prueksaritanont Thomayant , Lee Myung G. , Hsu Fung‐Hwa , Chiou Win L.
Published: October 2006

The oral absorption of iothalamate and the effect of amino acids on its absorption were studied in 6 dogs and 6 rats using a simple HPLC assay. The results showed that iothalamate was absorbed in dogs, averaging 9·9, 8·5, and 10·0 per cent following the administration of 40 and 100mg kg−1 of iothalamic acid capsules and 50mg kg−1 of sodium iothalamate solution, respectively. The absorption from the capsule was slower and more sustained than that from the solution. In rats, the absorption appeared to be dose‐independent (averaging about 4·2 per cent) in the dose range of 20–800 mg kg−1. The low bioavailability obtained was mainly due to the high polarity of iothalamate molecules as suggested by the GI recovery and in vitro partition studies. Among several amino acids tested as possible ion‐pair formers, only homoarginine hydrochloride increased the partition of iothalamate into chloroform layer. However, both homoarginine hydrochloride and arginine hydrochloride at the amino acid/iothalamate molar ratio of 25 were found to significantly enhance (about 70 per cent) the iothalamate absorption in dogs. The in situ rat small intestinal loop study indicated that the absorption‐enhancing effect of arginine was sodium dependent. At the sodium chloride concentration of 0·09 M, no significant increase in the absorption was observed, while at the concentration of 0·3 M or higher, a marked increase (about twofold) was obtained in both upper and lower intestine. Thus, the mechanism of the amino acids in facilitating the iothalamate absorption may be more closely related to the active amino acid transport system rather than the possible increase in lipophilicity of the ion‐pair formed. The potential use of such naturally occurring, relatively non‐toxic amino acids for increasing the GI absorption of water‐soluble weak acids or bases through ion‐pair formation remains to be fully investigated.
Mechanism for the interaction between triazolam and cimetidine
Authors: Cox Steven R. , Kroboth Patricia D. , Anderson Paul H. , Smith Randall B.
Published: October 2006

Four normal volunteers each received three intraduodenal infusions of 0·5 mg triazolam solutions. Three treatments were:

a pH 2·3 solution in which 47 per cent of the dose had hydrolysed to form a triazolo‐benzophenone (TB);

a pH 6·0 solution containing negligible TB;

the pH 6·0 solution administered during cimetidine treatment (1200mg day−1)

TB was stable in serum and only very low TB serum concentrations were observed from the pH 2·3 treatment. No difference was observed in any triazolam pharmacokinetic parameter between the pH 6·0 and the pH 2·3 treatments. Cimetidine increased the triazolam AUC∞ and Cmax by 54 and 35 per cent, respectively. These results indicate that TB undergoes extensive presystemic conversion to triazolam and the triazolam‐cimetidine interaction occurs primarily through a reduction in triazolam clearance.
Determination of isosorbide dinitrate biotransformation in various tissues of the rabbit by capillary column gas‐liquid chromatography
Authors: Tam G. S. , Nakatsu K. , Brien J. F. , Marks G. S.
Published: October 2006

A selective and sensitive capillary column gas‐liquid chromatographic procedure has been developed for the simultaneous determination of isosorbide dinitrate (ISDN) and its mononitrate metabolites in rabbit blood and tissue homogenates. The method has a limit of detection of 0.1 ng ml−1 for ISDN, 1 ng ml−1 for isososorbide 5‐mononitrate (5‐ISMN), and 2 ng ml−1 for isorbide 2‐mononitrate (2‐ISMN). The day‐to‐day coefficients of variation were 2.5, 6.8, and 11.3 per cent for ISDN, 5‐ISMN, and 2‐ISMN, respectively. The within‐day coefficients of variation were 2.7, 4.9 and 6.5 per cent for ISDN, 5‐ISMN, and 2‐ISMN, respectively. The procedure was used to determine the biotransformation of ISDN (2 × 10−7 M) to 5‐ISMN and 2‐ISMN by various rabbit tissue homogenates. The relative rate of biotransformation of ISDN was liver > lung ≈︁ intestine > kidney > blood ≈︁ skeletal muscle, with the lung and intestine homogenates being about two‐thirds as active as liver homogenates. These results indicate that extrahepatic biotransformation of ISDN, especially by lung and intestine, may contribute to the systemic clearance of ISDN in the rabbit.
Single dose pharmacokinetics of ketoprofen, indomethacin, and naproxen taken alone or with sucralfate
Authors: Caillé G. , du Souich P. , Gervais P. , Besner J.‐G.
Published: October 2006

The effects of sucralfate on the rate and extent of absorption of ketoprofen, indomethacin, and naproxen were investigated in healthy volunteers. Six volunteers each received sucralfate (2g) half an hour before a ketoprofen (50 mg) capsule, and, on another occasion, a ketoprofen (50 mg) capsule alone according to a 2 × 2 Latin square pattern of administration. The same design was used for studies with indomethacin (50 mg) capsules and naproxen (500 mg) tablets. Sucralfate decreased significantly (p < 0.05) the maximum plasma concentrations (Cmax) of ketoprofen, indomethacin, and naproxen. Although the time necessary to attain Cmax (tmax) for the three drugs tended to increase, only for indomethacin was this increase significant. Sucralfate decreased significantly the rate of absorption (ka) of naproxen and indomethacin, but not that of ketoprofen; it had no significant effect on the elimination half‐life and area under the plasma concentration as a function of time curves (AUC0→∞) of the three drugs.

Sucralfate thus decreases the Cmax and increases the tmax of ketoprofen, indomethacin, and naproxen without affecting their bioavailabilities.
Metabolic disposition of pyrazinamide in the rat: Identification of a novel in vivo metabolite common to both rat and human
Authors: Whitehouse L. W. , Lodge B. A. , By A. W. , Thomas B. H.
Published: October 2006

Only limited studies have been reported on the disposition and pharmacokinetics of pyrazinamide (PZA) in both animals and humans. The metabolism of PZA has never been completely elucidated, consequently the metabolites of PZA, pyrazinoic acid (PA), 5‐hydroxypyrazinoic acid (5‐HOPA), and 5‐hydroxypyrazinamide (5‐HOPZA) were characterized and the disposition of PZA was examined following administration of 150mg kg−1 of 14C‐PZA to male Wistar rats. Comparable t1/2 for total radiolabel 14C (1.45 ± 0.06h) and PZA (1.39 ± 0.04h) in the blood compartment were observed. Cumulative 48 h excretion in urine and faeces accounted for 82.6 ± 3.2 per cent and 11.0 ± 1.3 per cent, respectively, of the dose administered. In the 0‐6h urine collections PA, 5‐HOPA, 5‐HOPZA, and PZA, respectively, accounted for 25.4 ± 1.7, 17.7 ± 1.2, 11.6 ± 0.8, and 2.7 ± 0.2 per cent of the administered dose. In the 6–12 h urine samples the proportions of PA and 5‐HOPA increased statistically over the 0‐6h excretion whereas 5‐HOPZA decreased. Administration of PZA to humans indicated 5‐HOPZA was a major urinary metabolite in human. These data suggested that direct hydroxylation of PZA was an alternative pathway in the oxidation of PZA of importance to both human and rat.
Gastrointestinal metabolism of N‐acetylcysteine in the rat, including an assay for sulfite in biological systems
Authors: Cotgreave Ian A. , Berggren Margareta , Jones Thomas W. , Dawson Janet , Moldéus Peter
Published: October 2006

The intestinal metabolism of N‐acetylcysteine was studied in the rat. Isolated intestinal epithelial cells were shown to rapdily deacetylate [14C]‐N‐acetylcysteine to [14C]‐cysteine, with slight oxidation of the latter to disulfide species. The cells did not accumulate reduced or oxidized cysteine, and N‐acetylcysteine itself was not detected either free or in oxidized species intracellularly. Further metabolism of this NAC‐derived cysteine to inorganic sulfite or glutathione was not detected. Following the administration of [14C]‐N‐acetylcysteine (50mg/kg; 25μCi) in vivo into the ilium, small quantities of both reduced and oxidized [14C]‐N‐acetylcysteine were demonstrated in hepatic portal vein plasma. [14C]‐cysteine and inorganic sulfite were demonstrated as the major metabolites of N‐acetylcysteine. These were present in the portal vein plasma at levels five and three times greater than the parent drug, respectively, 30 min after dosing. Additionally, [14C]‐glutathione was shown to be a minor metabolite of N‐acetylcysteine accumulating in portal vein plasma.

These results may provide an explanation for the apparent low bioavailability of N‐acetylcysteine when administered orally in humans and are discussed in terms of the origins of the protective effect of the drug in cases of paracetamol intoxication in humans.
Single dose and steady‐state pharmacokinetics of adinazolam after oral administration to man
Authors: Wagner John G. , Rogge Mark C. , Natale Ronald B. , Albert Kenneth S. , Szpunar Gregory J.
Published: October 2006

An aqueous solution containing 1 mg of adinazolam mesylate per ml was administered orally as a single dose (40 mg) and with loading doses followed by hourly doses such that final dose rates of 1, 2, and 3 mg h−1 were administered to steady‐state. Four subjects exhibited linear steady‐state kinetics, while the other four exhibited Michaelis‐Menten kinetics, based on measurement by HPLC of both unchanged drug and the major N‐demethyl metabolite. The drug is very rapidly absorbed and has an intrinsic clearance of total (bound + free) drug which averaged 2.141 min−1 based on the steady‐state data and 1.171 min−1 based on the single dose data, but these means do not differ significantly. The apparent metabolite clearance, CLcm/fm (where fm = fraction of adinazolam converted to the N‐demethyl metabolite), averaged 0.1701 min−1 based on steady‐state data and 0.1791 min−1 based on single dose data and these means do not differ significantly. Pharmacokinetic parameters, such as these clearances, had large intersubject variations. Three types of bioavailabilities were estimated from the data.
Phenylpropanolamine pharmacokinetics in dogs after intravenous, oral, and oral controlled‐release doses
Authors: Hussain Munir A. , Aungst Bruce J. , Lam Gilbert , Shefter Eli
Published: October 2006

An adaption of a published high performance liquid chromatographic (HPLC) assay for phenylpropanolamine (PPA) in plasma was used to examine PPA pharmacokinetics in dogs. Plasma was extracted into ethyl acetate after the addition of 3.5 per cent sodium carbonate, and was then back‐extracted into aqueous acetic acid. The acetic acid was injected onto a cyano column using a mobile phase of acetonitrile, dilute hydrochloric acid, and sodium heptane sulfonate. Detection was by UV absorbance at 210 nm. The relative standard deviation of replicate assays averaged 5.2 per cent over a concentration range of 50‐1750 ng ml−1 plasma. PPA extraction recovery exceeded 90 per cent. The limit of detection was 30 ng ml−1 using 0.5 ml plasma and injecting 10μ.

PPA disposition was characterized in three dogs administered PPA i.v. and orally in immediate‐release and controlled‐release formulations. The terminal elimination half‐life averaged 3.5 ± 0.5 h after the i.v. dose. Oral absorption from the immediate‐release capsule was rapid and bioavailability was 98.2 ± 6.9 per cent. PPA absorption from the controlled‐release dosage form was biphasic; an initial rapid phase was followed by a second, slower absorption phase which continued over 16 h. Plasma PPA concentrations then declined with a half‐life roughly parallel to the i.v. and oral immediate‐release half‐lives. Oral bioavailability from the controlled release tablet was 93.7 ± 5.9 per cent.
Estimation problem due to multiple solutions in pharmacokinetic curve fitting to two‐compartment model and its avoidance
Authors: Murata Kazuo , Kohno Keiichi
Published: October 2006

A size of error in observed data for fitting curves and an estimation problem due to multiple solutions in a two‐compartment model were studied by using two different non‐linear least‐squares regression programs, SALS and NONLIN. It was found that bolus intravenous data have generally 5–10 per cent errors and oral data contain 10–25 per cent errors against the fitted data with respect to total 151 data sets of 11 different drugs. Parameters of five drugs reported in references were used to obtain simulated concentrations at the sampling times, and five different data sets containing 25 per cent normally distributed random errors as a coefficient of variation were generated using each data set of these simulated concentration. In the two‐compartment model with tri‐exponential equations, unreasonable estimates were occasionally observed, resulting in reversed relative values to the theoretical ones of L/M, L/N, M/N or Ka/α, which are analogous to the well‐known flip‐flop phenomenon in the one‐compartment model, when number of parameters to be estimated is not less than five or errors of data exceed about 10 per cent. In an attempt to avoid such unreasonable values, initial estimates for curve fitting was successfully obtained by using a microcomputer program SIMPLEX based on a simplex method. On the basis of these results, some problems in curve fitting of plasma drug concentration data are discussed.
Dissociation of authentic and artifactual effect of circulating heparin on drug protein binding
Authors: Dubé Louise M. , Davies Richard F. , Beanlands Donald S. , Mousseau Nicole , Beaudoin Nicole , Chan Beryl , Ho‐Ngoc Ann , McGilveray Iain J.
Published: October 2006

The purpose of this study was to dissociate the authentic and artifactual effect of in vivo heparin on drug protein binding using protamine as an inhibitor of ex vivo lipolysis. A mixture of ethylenediamine tetra‐acetic acid (EDTA, 5 mg ml−1) and protamine in the concentration range of 0 to 7·5 mg ml−1 was added to blood samples from 23 cardiac catheterized patients before (control) and 10 min after 3000 IU of intravenous heparin. In control samples, protamine does not interfere with the protein binding of lidocaine (L), quinidine (Q) or propranolol (P) when plasma pH is readjusted to 7·4. In the absence of protamine, heparin induced a significant increase in the free fraction by 40, 130, and 30 per cent for L, Q, and P, respectively (p < 0·001), while free fatty acid (FFA) levels increased 2 to 6 fold. When protamine was present, the heparin‐induced elevation in free fraction was significantly lower for L (16 per cent) and Q (77 per cent) but not for P; FFA levels were decreased at all protamine concentrations. Residual increases in free fraction and FFA levels compared to control values may represent the true in vivo effect of heparin at the peak activity of lipoprotein lipases. For L and Q, variations in free fraction were strongly associated with variations in FFA, but for P, no significant correlation was observed (r = 0·492). These results indicate that variations in free fraction of L and Q caused by heparin are, to a large extent, artifactual but may be prevented by use of protamine in collection tubes (5 to 7·5 mg ml−1). For P, the increase in free fraction was not mediated by variations of FFA indicating that another mechanism must be involved.
Bioequivalency of oral suspension formulations of cefixine
Authors: Faulkner Robert D. , Sia Louisa L. , Barone Joseph S. , Forbes St. J. , Silber B. Michael
Published: October 2006

A study was performed in 24 healthy male subjects to establish that two suspension formulations of cefixime were bioequivalent to each other and to a reference oral solution. A single 400mg oral dose of the drug was given in a randomized three‐way crossover design as two suspensions (a research suspension (RS) used during clinical trials and a suspension intended for marketing (MS)) and a reference oral solution (SOL). Each dose was separated from the other by a 3‐day washout period. Mean peak serum concentrations (Cmax) were 4·67, 4·10, and 4·27 μg ml−1 after the MS, RS, and SOL, respectively. Although comparison (ANOVA) of the mean pharmacokinetic parameters for cefixime found significant differences (p < 0·05) in Cmax, the time to Cmax, and area under the serum concentration time curve (AUC 0∞) values among the three formulations, the mean differences were less than 20 per cent. No significant differences (p > 0·05) were found in either the elimination half‐life or renal clearance of unchanged drug. Overall, with a 98 per cent power to detect a 20 per cent difference in AUC0→∞ or urinary recovery values between the formulations tested, the results show that the MS was bioequivalent to the RS and that both suspensions were bioequivalent to the SOL.
Release of 5‐fluorouracil from intramuscular w/o/w multiple emulsions
Authors: Omotosho J. A. , Whateley T. L. , Florence A. T.
Published: October 2006

Comparative in vivo studies of aqueous solution, multiple w/o/w, and w/o emulsions showed that formulating 5‐fluorouracil in emulsion systems significantly sustained the release of the drug from intramuscular injection sites in the rat.

Intramuscular injection of the drug in both w/o and w/o/w emulsion systems produced sustained blood concentrations with a later blood level peak than observed following intramuscular injection of aqueous solutions of the drug. The multiple w/o/w emulsion exhibited a more rapid release of drug from the injection site than the w/o emulsion because of partitioning of the drug to the external aqueous phase during secondary emulsification.

The fate of the oil phase following intramuscular injection of a water/hexadecane/water multiple emulsion spiked with 1‐14C‐hexadecane has been studied in rats as a function of stabilizer concentrations. Increasing the lipophilic surfactant (Span 80) concentration facilitated the clearance of the oily vehicle from the injection site, by mechanisms which remain to be elucidated.
Absorption kinetics of rectally and orally administered ibuprofen
Authors: Eller M. G. , Wright C. , Della‐Coletta A. A.
Published: October 2006

The bioavailability of rectally administered sodium ibuprofen solution and aluminum ibuprofen suspension was determined in eight normal subjects relative to the same treatments administered orally. The results indicate that the suspension was less bioavailable than the solution irrespective of the route of administration. Although not bioequivalent, rectally administered ibuprofen solution compared favourably with orally administered ibuprofen solution. The mean AUC and Cmax from rectal administration were 87 per cent and 62 per cent of the corresponding values achieved after oral administration. Mean residence times and peak times were 1–3 h longer with the rectal solution, indicating a slower rate of absorption. Absorption after rectal administration was zero order in some subjects while absorption after oral administration was first order. This may be due to the large differences in surface area between absorption sites. Since sodium ibuprofen solution is absorbed when given rectally, this route of administration could be used in patients unable to take oral ibuprofen.
Further observations on the disposition characteristics of salicylic acid in analbuminemic rats
Authors: Hirate Junji , Kato Yoshiteru , Horikoshi Isamu , Nagase Sumi , Ueda Clarence T.
Published: October 2006

The disposition characteristics of salicylic acid (SA) were investigated in analbuminemic rats after intravenous bolus injection of 10 and 173 mg kg−1 of SA to study the effects of plasma protein binding on drug disposition. Following the administration of 10 mg kg−1 of SA, total body SA clearance (CL) was markedly faster and its apparent volume of distribution (Vd) significantly greater in the analbuminemic rats in comparison to the controls. Further, the apparent elimination rate constant (kj) was two‐fold greater and the corresponding elimination half‐life (t1/2) shorter in the rats with low plasma albumin. Whole body autoradiograms obtained following the administration of 14C‐salicylic acid demonstrated that the tissue distribution of SA was greater in the analbuminemic rats which was in agreement with the larger Vd observed in this group of rats. After the administration of 173 mg kg−1 of SA, no differences in CL, Vd, kj or t1/2 were noted between the analbuminemic and control rats. Dose‐dependent SA disposition was observed in both the analbuminemic and control rats with the effects being more pronounced in the rats with low plasma albumin. The results suggested that the disposition characteristics of SA were markedly altered in the presence of low plasma albumin concentrations due to reduced plasma SA protein binding.
Multiple dose comparison of a whole 240 mg verapamil sustained‐release tablet with two half tablets
Authors: Moreland T. A. , McMurdo M. E. T. , McEwen J.
Published: October 2006

Twelve healthy male volunteers were studied in a balanced crossover comparison of an intact 240 mg verapamil sustained‐release tablet (Securon SR, Isoptin Forte Retard) given once daily for 7 days, and the same dose given as two half tablets. One subject was withdrawn because of asymptomatic second degree heart block on day 3 of verapamil treatment. The mean Cmax after dosing with whole tablets, 143 (95 per cent confidence limits 91·6–223) ngml−1 was lower than after dosing with half tablets, 160 (107–241) ngml−1, but this was not significant (p=0·49). The mean steady‐state Cmin values after whole and half tablets were also similar: 22·2 (12·6–39·4) ngml−1 and 22·0 (16·2–29·9) ngml−1, respectively (p=0·96). The mean (± S.D.) tmax, AUC0–24 and t1/2 were not significantly different: whole tablet 3·5 ± 1·2h, 1733 ± 1125 ng.h ml−1 and 10·5 ± 3·4h, respectively, and half tablets 3·6 ± 1·0h, 1780 ± 1057 ng.h ml−1 and 9·6 ± 2·3h, respectively. The findings for plasma norverapamil were generally similar to those for the parent drug. This investigation indicates that the formulation is sufficiently robust to retain its sustained‐release properties when the tablet is halved.
Absorption kinetics of topical clindamycin preparations
Authors: Eller Mark G. , Smith Randal L. B. , Phillips J. Paul
Published: October 2006

Systemic clindamycin absorption was examined in 12 male Caucasians without acne who recieved 1 ml of Cleocin‐T® and 1 ml of 1 per cent clindamycin HCl in Vehicle‐N® (Neutrogena) applied topically the face every 12 h for 4 days according to a crossover design. In a separate phase clindamycin phosphate was administered by an IV infusion of 300 mg over 10 min. Systemic absorption was much higher with clindamycin in Vehicle‐N than with Cleocin‐T. Absolute bioavailability calculated from cumulative urinary excretion and serum AUCs were in good agreement and averaged 1·7 per cent and 7·5 per cent for Cleocin‐T and clindamycin in Vehicle‐N, respectively. Peak serum concentrations ranged from less than 0·5 ng ml−1 to 6 ng ml−1 for Cleocin‐T and from 4–20 ng ml−1 for clindamycin in Vehicle‐N. Absorption profiles indicated zero order absorption with Cleocin‐T. No appreciable systemic accumulation from the repeated topical applications was noted. Systemic exposure to clindamycin from these formulations is minimal.
Investigation of mezlocillin disposition with a porcine model
Authors: Dipiro Dr Joseph T. , Davis John B. , Boudinot F. Douglas , Cheung Richard P. F. , Sisley John F.
Published: October 2006

The suitability of the pig as an animal model for mezlocillin disposition was assessed. Serum, urine, and bile were collected after the administration of 50, 100 and 200 mg kg−1 mezlocillin to pigs and drug pharmacokinetics were characterized. Mezlocillin concentrations in biological fluids were determined by HPLC and free mezlocillin was determined by ultrafiltration. The pharmacokinetics of mezlocillin appeared to be independent of dose over the dosage range studied. Total clearance, renal clearance, and biliary clearance were 0·18 (0·05) 1 h−1 kg−1, 0·13 (0·03) 1 h−1 kg−1, and 0·07 (0·02) 1 h−1 kg−1, respectively. The steady‐state volume of distribution was 0·29 (0·08) 1 kg−1. The pharmacokinetic parameters determined in the porcine model are similar to those reported for health human volunteers. Therefore, this model appears suitable for the study of mezlocillin disposition, and may be applied to the study of other agents that are appreciably biliary excreted.
Interspecies pharmacokinetic scaling of metazosin, a novel alpha‐adrenergic antagonist
Authors: Lapka Roman , Rejholec Václav , Sechser Tomás , Peterková Marcela , Šmíd Milan
Published: October 2006

Based on pharmacokinetic data from mice, rats, and rabbits the prediction of pharmacokinetics of intravenous metazosin in man has been performed. The correlations were based upon allometric scaling of plasma clearance and the volume of distribution at steady‐state. A one‐compartment body model approximating clinical pharmacokinetics fits well the elimination phase of subsequently measured metazosin concentrations in volunteers. Fitting human pharmacokinetic data to allometric equations enabled us to superimpose pharmacokinetic curves from different species.
Simulation of the hepatic metabolism of stilbene and its tricyclic derivatives by fenton and ruff reagents: Models for cytochrome P‐450 activation of chemical carcinogens
Authors: Zbaida Shumel , Kariv Rami
Published: October 2006

Reactions of trans‐stilbene, cis‐stilbene, 5H‐dibenzo [a, d] cyclo‐heptene 5‐one and 5H‐dibenz [b, f] azepine (iminostilbene) with Fenton reagent [Fe (II)/H2O2] clearly simulate their hepatic metabolism. Epoxidation on the corresponding ethylenic linkage was found to be a common pathway of these compounds. Epoxides of trans‐stilbene, cis‐stilbene, and 5H‐dibenzo[a, d]cycloheptene 5‐one were further oxidized to dihydrodiols, α‐hydroxyketones, diketones, and finally cleavage of the ethylenic bonds to the formation of the corresponding aldehydes. However, the unstable epoxide of iminostilbene gave 9‐acridinecarbaldehyde that is further oxidized to 9‐acridone.

Reaction of both trans‐ and cis‐stilbene with Ruff reagent [Fe III/H2O2] gave the same oxidative products to that obtained from Fenton reagent. The radical scavenger 2,6 bis (1,1‐dimethylethyl)‐4‐methyl phenol (BHT) decreases the total yield conversion and increases the formation ratio of both cis‐epoxide and d, l‐hydrobenzoin from cis‐stilbene.
A computer simulation of the food effect: Transient changes in hepatic blood flow and michaelis‐menten parameters as mediators of hepatic first pass metabolism and bioavailability of propranolol
Authors: Semple H. A. , Tam Y. K. , Coutts R. T.
Published: October 2006

A physiological model of propranolol disposition was designed to help explain the large increase in AUC seen when the drug is administered with food. The mass balance equation for the liver compartment used Michaelis‐Menten terms to describe hepatic metabolism. Previously published pharmacokinetic and physiological parameters were used throughout. The three parameters, Qh, Kmt, and Vmax, were varied for different durations and by a factor of two to increase AUC. The parameter variations were patterned after the changes in splanchnic blood flow following a high protein meal.

The model exhibits saturation kinetics for most of the absorption phase after a simulated single oral dose of 1 mg kg1, during which hepatic extraction is decreased. As the dose is decreased, the degree of saturation lessens. Using an input rate representative of regular release, changes to Qh caused little change in AUC. While the model was moderately sensitive to Kmt changes, large increases in AUC were seen after Vmax was altered. The sensitivity of the system to Kmt and Vmax changes became greater as the duration of the changes was increased. The AUC was most sensitive to Vmax variation, leading to the conclusion that mechanisms involving this parameter should be explored further. Reducing the input rate to mimic sustained release decreased the AUC for a given dose as well as the sensitivity of AUC to changes in Kmt and Vmax.