ABSTRACT
The biotransformation and tissue distribution of 9-cis-retinoic acid was investigated in hairless rats. Indeed, only limited information is available about the pharmacokinetics of 9-cis-retinoic acid. Assuming that the target site for retinoids is the skin, tissue distribution study is therefore particularly justified. Following single oral administration of 30 mg/kg of 9-cis-retinoic acid, the parent drug and five metabolites were detected in plasma. Additionally, concentrations of 9-cis-retinoic acid and metabolites were determined in the skin and seven other tissues. The distribution of 9-cis-retinoic acid was rapid in all of the organs studied (T(max)
Subject(s)
Antineoplastic Agents/pharmacokinetics , Tretinoin/pharmacokinetics , Alitretinoin , Animals , Antineoplastic Agents/blood , Biotransformation , Chromatography, High Pressure Liquid , Male , Rats , Skin/metabolism , Tissue Distribution , Tretinoin/bloodABSTRACT
Cytochrome P450 expression in liver is influenced by several factors, including species, sex and strain. We compared metabolism formation of clozapine in different species (rat, mouse, guinea-pig, dog, monkey and man) so as to choose between species to further validate interaction studies. Liver microsomes of male and female Sprague-Dawley rats, hairless rats, OF1 mice, Balb C mice and Dunkin-Hartley albino guinea-pigs, male beagle dogs, male cynomolgus monkeys and man were used to investigate in vitro metabolism of clozapine. This process was dependent on the presence of NADPH and on the presence of microsome protein. In addition, we observed the formation of desmethyl- and N-oxide metabolites, with the rate of formation of each of these compounds varying with species, sex and strain of microsomes incubated. The desmethyl- and N-oxide metabolites formed were statistically greater in male than in female rats, mice in the two strains studied, as well as for the guinea-pigs. Levels of desmethyl clozapine formed were high for the rats and no significant difference in clozapine biotransformation was observed between Sprague-Dawley and hairless rats. For man, the formation of metabolites of clozapine was comparable with guinea-pig, dog and monkey. In addition, we screened the effect of 52 molecules, representative of 11 different therapeutic classes, on the metabolism of clozapine by rat liver microsomes. We found that most of the calcium channel blockers (diltiazem, felodipine, isradipine, lacidipine, nicardipine and nitrendipine), antifungals (ketoconazole, miconazole) and two anticancer drugs (paclitaxel, teniposide) caused more than 50% inhibition of clozapine metabolism in vitro. The extent of inhibition was increased in a concentration-dependant manner. Complementary clinical and pharmacokinetic studies should be performed to confirm these results.
Subject(s)
Clozapine/metabolism , Microsomes, Liver/metabolism , Animals , Clozapine/analogs & derivatives , Clozapine/antagonists & inhibitors , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Drug Interactions , Drug-Related Side Effects and Adverse Reactions , Female , Guinea Pigs , Humans , Macaca fascicularis , Male , Mice , Mice, Inbred BALB C , Microsomes, Liver/drug effects , NADP/pharmacology , Rats , Rats, Nude , Rats, Sprague-Dawley , Sex Factors , Species SpecificityABSTRACT
We have studied excretion of oral 9-cis-retinoic acid in urine and feces in vigil rats and in bile in anesthetized rats. A proportion of 53 +/- 13% of the dose of 9-cis-retinoic acid administered was eliminated through the feces in 72 hr, and the urinary excretion was negligible. The prevalent form of elimination in feces and urine was the unchanged compound. Low biliary excretion was, for the most part, composed of metabolites.
Subject(s)
Tretinoin/pharmacokinetics , Administration, Oral , Alitretinoin , Animals , Bile/metabolism , Chromatography, High Pressure Liquid , Male , Rats , Rats, Wistar , Tretinoin/administration & dosage , Tretinoin/urineABSTRACT
A gradient reversed-phase high-performance liquid chromatographic technique is described for the easy separation and quantification of some retinoids; all-trans-retinoic acid, 13-cis-retinoic acid, 9-cis-retinoic acid and their corresponding 4-oxometabolites, in plasma. The method involved a diethyl ether-ethyl acetate (50:50, v/v) mixture extraction at pH 7 with acitretin and 13-cis-acitretin as internal standards. A Nova-Pak C18 steel cartridge column was used. The mobile phase was methanol-acetonitrile (65:35, v/v) and 5% tetrahydrofuran (solvent A) and 2% aqueous acetic acid (solvent B) at 1 ml/min. The gradient composition was (only the percentages of solvent B are mentioned): I, 25% solvent B at the time of injection; II, 12% solvent B at 11 min until min; III, 25% solvent B and maintenance of 25% solvent B for 10 min until a new injection. Total time between injections was 40 min. Detection was by absorbance at 350 nm. The precision calculated for plasma concentrations ranging from 2 to 250 ng/ml was better than 15% and the accuracy was less than 12%. The linearity of the method was in the range of 2 to 400 ng/ml of plasma. The limit of quantification was 2 ng/ml for each of the compounds. The HPLC method was applied to plasma specimens collected from animals receiving single dose administrations of all-trans-retinoic acid, 13-cis-retinoic acid and 9-cis-retinoic acid.
