RT Journal Article
SR Electronic
T1 THE CHIMPANZEE (<em>PAN TROGLODYTES</em>) AS A PHARMACOKINETIC MODEL FOR SELECTION OF DRUG CANDIDATES: MODEL CHARACTERIZATION AND APPLICATION
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1359
OP 1369
DO 10.1124/dmd.104.000943
VO 32
IS 12
A1 Harvey Wong
A1 Scott J. Grossman
A1 Stephen A. Bai
A1 Sharon Diamond
A1 Matthew R. Wright
A1 James E. Grace, Jr.
A1 Mingxin Qian
A1 Kan He
A1 Krishnaswamy Yeleswaram
A1 David D. Christ
YR 2004
UL http://dmd.aspetjournals.org/content/32/12/1359.abstract
AB 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 6β-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. The American Society for Pharmacology and Experimental Therapeutics