bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractCrotethamide 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

AbstractAn 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

AbstractThe 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

AbstractFour 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

AbstractA 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

AbstractThe 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

AbstractOnly 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

AbstractThe 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

AbstractAn 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

AbstractAn 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

AbstractA 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

AbstractThe 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

AbstractA 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

AbstractComparative 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

AbstractThe 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

AbstractThe 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.