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The present study is concerned with the absorption and disposition of a tripeptoid (N-substituted glycine derivative) and a tetrapeptide in the rat. The two compounds have similar backbone structures but differ with respect to the presence or absence of peptide bond. [3H]tripeptoid and [3H]tetrapeptide were administered orally (30 mg kg(-1)) and intravenously (i.v.) (30 or 3 mg kg(-1)) to Sprague Dawley rats. Blood, urine and feces were collected at designated times for radioactivity and parent drug analysis. The intestinal absorptive clearances of the tripeptoid and tetrapeptide were studied using an in situ rat intestinal perfusion model. The octanol/water partition coefficient of these two compounds was also determined. The results showed that the peptoid and peptide have similar absorptive clearance and octanol/water partitioning, but different in vivo absorption and disposition characteristics. The absorptive clearances of the tripeptoid and tetrapeptide were 6.7 and 4.8 x 10(-4) mL min(-1) cm(-1), respectively, and the corresponding octanol/water partition coefficients were 0.39 and 0.30. The extent of oral absorption of the tripeptoid was only 3-8%, consistent with its low absorptive clearance. In contrast, the apparent absorption of the tetrapeptide was > 75% of the radioactive dose. The peptide was completely metabolized within 2 h after an i.v. dose, whereas the peptoid was stable in blood and was primarily eliminated in feces as intact drug. In conclusion, the difference in in vivo absorption and disposition between the peptoid and peptide was apparently due to the presence or absence of a peptide bond. The tetrapeptide was subject to rapid metabolism in the body. Its relatively high absorption appeared to represent the absorption of metabolized radioactive fragments. The peptoid appears to have advantages over the peptide in term of metabolic stability, but its low oral absorption and rapid biliary excretion present additional challenges in the selection of an optimal drug candidate.

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Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, was metabolized by human liver microsomes to 5-hydroxy-, 6-hydroxy-, and N-deisopropyl-fluvastatin. Total metabolite formation was biphasic with apparent Km values of 0.2 to 0.7 and 7.9 to 50 microM and intrinsic metabolic clearance rates of 1.4 to 4 and 0.3 to 1.5 ml/h/mg microsomal protein for the high and low Km components, respectively. Several enzymes, but mainly CYP2C9, catalyzed fluvastatin metabolism. Only CYP2C9 inhibitors such as sulfaphenazole inhibited the formation of both 6-hydroxy- and N-deisopropyl-fluvastatin. 5-Hydroxy-fluvastatin formation was reduced by compounds that are inhibitors of CYP2C9, CYP3A, or CYP2C8. Fluvastatin in turn inhibited CYP2C9-catalyzed tolbutamide and diclofenac hydroxylation with Ki values of 0.3 and 0.5 microM, respectively. For CYP2C8-catalyzed 6alpha-hydroxy-paclitaxel formation the IC50 was 20 microM and for CYP1A2, CYP2C19, and CYP3A catalyzed reactions, no IC50 could be determined up to 100 microM fluvastatin. All three fluvastatin metabolites were also formed by recombinant CYP2C9, whereas CYP1A1, CYP2C8, CYP2D6, and CYP3A4 produced only 5-hydroxy-fluvastatin. Km values were approximately 1, 2.8, and 7.1 microM for CYP2C9, CYP2C8, and CYP3A, respectively. No difference in fluvastatin metabolism was found between the CYP2C9R144 and CYP2C9C144 alleles, suggesting the absence of polymorphic fluvastatin metabolism by these alleles. CYP1A2, CYP2A6, CYP2B6, CYP2C19, CYP2E1, and CYP3A5 did not produce detectable amounts of any metabolite. This data indicates that several human cytochrome P-450 enzymes metabolize fluvastatin with CYP2C9 contributing 50-80%. Any coadministered drug would therefore only partially reduce the metabolic clearance of fluvastatin; therefore, the likelihood for serious metabolic drug interactions is expected to be minimal.

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