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THE CHIMPANZEE (PAN TROGLODYTES) AS A PHARMACOKINETIC MODEL FOR SELECTION OF DRUG CANDIDATES: MODEL CHARACTERIZATION AND APPLICATION

Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, Wilmington, Delaware (D.D.C., S.D., K.Y.), Newark, Delaware (M.R.W.), Wallingford, Connecticut (H.W., J.E.G.), and Princeton, New Jersey (S.J.G., S.A.B., M.Q., K.H.)

The chimpanzee (CHP) was evaluated as a pharmacokinetic model for humans (HUMs) using propranolol, verapamil, theophylline, and 12 proprietary compounds. Species differences were observed in the systemic clearance of theophylline (5-fold higher in CHPs), a low clearance compound, and the bioavailability of propranolol and verapamil (lower in CHPs), both high clearance compounds. The systemic clearance of propranolol (1.53 l/h/kg) suggested that the hepatic blood flow in CHPs is comparable to that in humans. No substantial differences were observed in the in vitro protein binding. A preliminary attempt was made to characterize cytochrome P450 (P450) activities in CHP and HUM liver microsomes. Testosterone 6ß-hydroxylation and tolbutamide methylhydroxylation activities were comparable in CHP and HUM liver microsomes. In contrast, dextromethorphan O-demethylation and phenacetin O-deethylation activities were 10-fold higher (per mg protein) in CHP liver microsomes. Intrinsic clearance estimates in CHP liver microsomes were higher for propranolol (10-fold) and theophylline (5-fold) and similar for verapamil. Of the 12 proprietary compounds, 3 had oral clearances that differed in the two species by more than 3-fold, an acceptable range for biological variability. Most of the observed differences are consistent with species differences in P450 enzyme activity. Oral clearances of proprietary compounds in HUMs were significantly correlated to those from CHPs (r = 0.68; p = 0.015), but not to estimates from rat, dog, and monkey. In summary, the chimpanzee serves as a valuable surrogate model for human pharmacokinetics, especially when species differences in P450 enzyme activity are considered.

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