The chimpanzee (Pan troglodytes) as a pharmacokinetic model for selection of drug candidates: model characterization and application.
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 (approximately 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 (approximately 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 6beta-hydroxylation and tolbutamide methylhydroxylation activities were comparable in CHP and HUM liver microsomes. In contrast, dextromethorphan O-demethylation and phenacetin O-deethylation activities were approximately 10-fold higher (per mg protein) in CHP liver microsomes. Intrinsic clearance estimates in CHP liver microsomes were higher for propranolol (approximately 10-fold) and theophylline (approximately 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.
Wong
Harvey
H
Discovery Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492-7660, USA. harvey.wong@bms.com
Grossman
Scott J
SJ
Bai
Stephen A
SA
Diamond
Sharon
S
Wright
Matthew R
MR
Grace
James E
JE
Qian
Mingxin
M
He
Kan
K
Yeleswaram
Krishnaswamy
K
Christ
David D
DD
D000082:Acetaminophen / Q000493:pharmacokinetics; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics; D018712:Analgesics, Non-Narcotic / Q000493:pharmacokinetics; D000818:Animals; D015153:Blotting, Western; D001993:Bronchodilator Agents / Q000493:pharmacokinetics; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000378:metabolism; D008954:Models, Biological; D002679:Pan troglodytes / Q000502:physiology*; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D011433:Propranolol / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet; D013806:Theophylline / Q000493:pharmacokinetics; D014700:Verapamil / Q000493:pharmacokinetics
D000319:Adrenergic beta-Antagonists; D018712:Analgesics, Non-Narcotic; D001993:Bronchodilator Agents; D002121:Calcium Channel Blockers; D004364:Pharmaceutical Preparations; D000082:Acetaminophen; D011433:Propranolol; D013806:Theophylline; D014700:Verapamil