bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bioavailability of medroxalol in man
Authors: Keeley Frederick J. , Weiner Daniel L. , Okerholm Richard A. 
Published: October 2006

AbstractTen healthy male volunteers received single oral doses of 100 mg of medroxalol administered as a solution, a preliminary tablet formulation and a single dose of 100 mg administered intravenously in a randomized three‐way crossover study. Mean terminal half‐lives of 12·4, 134, and 11·3 h were observed for the intravenous, solution and tablet formulation, respectively.Mean urinary recovery of parent drug at 48 h was 8·9 per cent, 3·9 per cent, and 3·2 per cent. Absolute bioavailability estimated from plasma AUC was 54 per cent for the solution and 38 per cent for the tablet, and the relative bioavailability from the tablet was 71 per cent.
Measurement of plasma concentrations of vasodilators and metabolites by the tea analyzer
Authors: Yu W. C. , Goff E. U. 
Published: October 2006

AbstractThe determination of therapeutic levels of glyceryl trinitrate (GTN), isosorbide dinitrate (ISDN), pentaerythritol tetranitrate (PETN), and their metabolites in human plasma was conducted using the TEA Analyzer interfaced to a high‐performance liquid chromatograph (HPLC‐TEA). Chromatographic separation of these compounds was accomplished under isocratic HPLC conditions.The sensitivity of the instrument was established to be 0·1 ng for each of the three nitrate esters.At the Sngml−1 plasma fortification level, the precision of the method gives mean relative standard deviations (RSD) of ± 10·2 per cent, ± 6·5 per cent, and ± 5·9 per cent for GTN, ISDN, and PETN, respectively.The recoveries for the nitrate esters and their metabolites from human plasma over the range 1·50ng ml−1 are presented.The specific and sensitive HPLC‐TEA method developed in this study provides a reliable and rapid assay for the routine analysis for metabolism or bioavailability studies of nitrate esters and their metabolites in plasma of blood, with a detection limit as low as 1 ng ml−1.
Preliminary observations on dissolution and bioavailability of triamterene–hydrochlorothiazide combination products
Authors: Shah Vinod P. , Walker Mark A. , Prasad Vadlamani K. , Lin Julianne , Knapp Gene , Cabana Bernard E. 
Published: October 2006

AbstractThe dissolution profiles of two brands of triamterene–hydrocholorthiazide (TRM–HCT) combination tablets and two brands of TRM–HCT combination capsules were studied using the USP paddle method at 100 rev min−1 in acid medium (0·1 N). The tablets represent two products marketed in Germany, whereas the capsules represent the approved innovator's product and an unapproved generic product. The tablets dissolved almost 100 per cent in 15 min whereas the capsules dissolved less than 25 per cent in 60 min. A pilot bioavailability study was carried out in four normal healthy male volunteers. Urine samples were collected over a 48 h period and analysed for TRM, its major metabolite TRM‐sulfate, and HCT using HPLC methods. The dissolution characteristics of TRM can be associated with the total drug excretion (absorption) of the product. On the other hand, the excretion (absorption) of HCT was independent of dissolution characteristics of the products. However, in TRM–HCT combination product, there appears to be a 50 per cent reduction in HCT excretion (absorption) when compared to the reported excretion (absorption) from a marketed single‐entity product.
Pharmacokinetics and bioavailability of theophylline following enema and suppository admininstration in man
Authors: Cole Mohammed L. , Kunka Robert L. 
Published: October 2006

AbstractThe pharmacokinetics and bioavailability of theophylline from a commercial oral elixir of theophylline, a rectal suppository of aminophylline, and a rectal enema of theophylline monoethanolamine was compared in six normal subjects. Using a complete crossovver design, the fasted subjects received a single dose of each dosage form. Blood and saliva samples were collected at frequent time intervals for 24 h, and the plasma assayed for theophylline by a specific thin‐layer chromatography densitometric method. No statistically significant differences existed among the three dosage forms with respect to Cmax and AUC corrected for the elimination rate constant and the dose (mg kg−1). However, tmax was significantly larger for the suppository. While the rate of absorption was significantly slower for the suppository, no differences in the extent of absorption existed among the three dosage forms. A one‐compartment open model with apparent first‐order absorption adequately described the plasma concentration–time data for the elixir and enema, whereas the suppository data were best fitted by a one‐compartment open model with apparent zero‐order absorption and a lag time. A rate‐limiting, concentration‐independent release of drug from the base most likely accounts for the slow absorption of theophylline from the suppository. While the saliva: plasma ratio remained fairly constant for most of the study period, the large variability found during the absorption phase following drug administration limits the usefulness of this parameter as a monitor of theophylline plasma concentrations.
Pharmacokinetics of diazepam from a controlled release capsule in healthy elderly volunteers
Authors: Wills Robert J. 
Published: October 2006

AbstractA 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

AbstractEnalapril, 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

AbstractFlow 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

AbstractThe 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

AbstractThe 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

AbstractThe 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

AbstractThe 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

AbstractBioavailability 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

AbstractA 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

AbstractLidocaine 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

AbstractA 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

AbstractSingle 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

AbstractThe 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

AbstractEleven 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’.