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Biomedical subjects

G R Wilkinson

Publications and source records attributed to G R Wilkinson.

195 records · Page 11Linked to original sources
PubMedDate not supplied

Disposition of carbamazepine and its 10,11-epoxide metabolite in the isolated perfused rat liver.

The disposition of carbamazepine and its metabolite, the 10,11-epoxide, was investigated in isolated perfused livers from control and phenobarbital-pretreated rats. The mean hepatic clearance of carbamazepine was 0.28 ml per min per g of liver corresponding to a mean extraction ratio of 0.16 and a mean intrinsic clearance of 0.33 ml per min g of liver. In phenobarbital-pretreated rats, there was an approximately 40% increase in the hepatic clearance due to a concomitant increase in the mean extraction ratio from 0.16 to 0.26. The carbamazepine-10,11-epoxide generated in the liver approached and attained its peak concentration more rapidly in pretreated than in control rat livers. In the latter group there was virtually no disappearance of the epoxide from the perfusate, whereas in the pretreated rat livers the perfusate concentrations declined after 90 min. The extremely low clearance of the epoxide generated by metabolism in control rat liver was confirmed by administration of the epoxide per se to the perfusion system. The mean extraction ratio of the epoxide in this situation was only 0.016 and it was unaffected by prior treatment of the rats with phenobarbital. However, the epoxids exhibited dose-dependent kinetics with a 3-fold increase in the extraction ratio when the administered dose was reduced from 500 to 166 microng. The observed induction of the hepatic clearance of carbamazepine is supportive of the involvement of this mechanism in the interaction of this drug with various other anticonvulsants in both children and adults.

Animals↗
PubMedDate not supplied

Geometric isomerization of doxepin during its N-demethylation in humans.

The N-demethylation of the individual Z-(cis) and E-(trans) isomers of the tricyclic antidepressant doxepin was studied by examining the 0-8 hr serum concentration-time and the 0-72 hr urinary excretion profiles of parent drug and metabolite in eight healthy males who had received a single oral dose consisting of 25 mg each of Z-[2H0]- and E-[2H4]-labeled drug as the hydrochloride salt. Interconversion of doxepin's isomers was not observed but stereoselective excretion was present. Significant amounts of Z-N-desmethyldoxepin were formed and excreted after dosing with E-doxepin, the urinary Z/E ratio ranging from 0.08 to 3.06. A small amount of nondeuterated E-N-desmethyldoxepin was formed from Z-doxepin in most, but not all, subjects. These findings indicate that isomerization occurs during the N-demethylation of doxepin, possibly involving the formation of an intermediate in which the exocyclic double bond is hydrated and then subseqently dehydrated. This novel biotransformation process accounts for the observation that the Z/E plasma concentration ratio of N-desmethyldoxepin is often greater than that of the administered doxepin in patients receiving the drug therapeutically.

Adult↗
PubMedDate not supplied

Diazepam disposition in mature and aged rabbits and rats.

The disposition of diazepam after intravenous administration was investigated in mature young and old female Dutch Belted rabbits (1-1.5 and 5.6.5 years) and Fischer-344 rats (6 and 30 months) to determine whether they exhibited an age-related increase in distribution similar to that previously observed in the human. No significant differences were found in the pharmacokinetic behavior of diazepam or its N,-demethylated metabolite between the young and old rabbits, although there was a suggestion that clearance might have been impaired in the older animals. In contrast, the initial postequilibrium and steady-state volumes of distribution of diazepam were higher in the old rat, but only the latter was statistically significant when adjusted for body weight. No significant differences were found in other pharmacokinetic parameters including plasma binding, nor were the metabolite concentration/time profiles different. The increased steady-state distribution volume could reflect a change in lean body mass/body in the old rat. However, the magnitude of the distributional change (50%) in small fat ratio compared to that in humans (300-400%) and this precludes the female fisher-344 rat as a suitable animal model for further investigation of the effects of age on the distribution of the benzodiazepines.

Age Factors↗
PubMedDate not supplied

Hepatic elimination in the rat of ditekiren (U-71038), a renin inhibitor pseudohexapeptide.

Oligopeptides developed as potential therapeutic agents are often limited in their duration of action because of rapid disappearance from the bloodstream, even if they are proteolytically stable. In a number of instances, this involves hepatic elimination via biliary excretion of intact peptide. Knowledge of the processes of such hepatic uptake and secretion and their characteristics is limited. Accordingly, the disposition of the renin inhibitor ditekiren--a pseudohexapeptide used as a model agent--was investigated in the isolated perfused rat liver preparation. Disappearance of radioactivity from the perfusate after the rapid addition of a radiolabeled tracer dose (0.11 micrograms) of ditekiren was biexponential. The concomitant administration of increasing doses of unlabeled oligopeptide (0.25 to 5 mg) had no effect on the perfusate's pharmacokinetic parameters, including clearance, 6.82 +/- 0.88 ml/min (mean +/- SD) at a perfusate flow rate of 10 ml/min. However, at the 10 mg dosage level, the concentration-time profile became monoexponential with a half-life of 1.24 +/- 0.48 hr--a value similar to the terminal rate of elimination at lower dosages--and perfusate clearance was reduced by 82%. By contrast, marked dose-dependent changes in the biliary excretion of intact ditekiren were observed when unlabeled doses from 0.25 to 10 mg were administered: the 0 to 2 hr biliary recovery decreasing from 61.7 +/- 8.9 to 4.3 +/- 1.8%. These findings demonstrate that both the initial uptake into hepatocytes and the subsequent biliary excretion of a linear oligopeptide, such as ditekiren, are nonlinear. This suggests that translocation across the basolateral (sinusoidal) and canalicular membranes involves carrier-mediated processes.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗