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Predicting the hepatic clearance of xenobiotics in humans from in vitro data

✍ Scribed by Betty-Ann Hoener

Publisher
John Wiley and Sons
Year
1994
Tongue
English
Weight
449 KB
Volume
15
Category
Article
ISSN
0142-2782

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✦ Synopsis

Values for V,, and K, determined during the in vitro metabolism of a xenobiotic to a known metabolite by a specific human isozyme of cytochrome P450 (P450) were used to predict the hepatic clearance (CLH) of the xenobiotic to that metabolite. The calculated CLH values were then compared to literature values of clearance (CL) to the same metabolite obtained during pharmacokinetic studies in humans. For the 6-hydroxylation of chlorzoxazone (P450 2E1) the predicted and actual clearances were 110 & 77 mL min-' and 110 mL min-I, respectively. For the 6P-hydroxylation of cortisol, the deethylation of lidocaine (two studies), and the oxidation of nifedipine (all P450 3A3/4) the values were 13 2 15 mL min-I and 13 mL min-I; 758 k282 or 8292 283 mL min-l and 875 mL minl; and 284& 176 mL min-I and 294 mL min-I, respectively. An increase to 72 2 25 mL min-in the CLH of cortisol to 6P-hydroxycortisol was calculated following rifampicin treatment. Finally, the polymorphic nature of the metabolism (P450 2D6) of mexiletine was confirmed. The usefulness of the method and its limitations are discussed.

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