Preclinical metabolism and pharmacokinetics of NVS-CRF38, a potent and orally bioavailable corticotropin-releasing factor receptor 1 antagonist.
1. The pharmacokinetic properties and metabolism of NVS-CRF38 [7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo[5,1-b]oxazole], a novel corticotropin-releasing factor receptor 1 (CRF1) antagonist, were determined in vitro and in animals. 2.  NVS-CRF38 undergoes near complete absorption in rats and dogs. In both species the compound has low hepatic extraction and is extensively distributed to tissues. 3. In rat and human hepatic microsomes and cryopreserved hepatocytes from rat, dog, monkey and human, NVS-CRF38 was metabolised to form O-desmethyl NVS-CRF38 (M7) and several oxygen adducts (M1, M3, M4, M5 and M6). In hepatocytes further metabolites were observed, specifically the carboxylic acid (M2) and conjugates (sulphate and glucuronide) of M7. 4.  Formation of primary metabolites in hepatocytes was blocked by the cytochrome P450 enzyme (P450) suicide inhibitor 1-aminobenzotriazole, implicating P450 enzymes in the primary metabolism of this compound. 5. NVS-CRF38 is weakly bound to plasma proteins from rat (fub = 0.19), dog (fub = 0.25), monkey (fub = 0.20) and humans (fub = 0.23). Blood-to-plasma partition for NVS-CRF38 approaches unity in rat and human blood. 6.  The hepatic clearance of NVS-CRF38 in humans is predicted to be low (extraction ratio ∼ 0.2) based on scaling from drug depletion profiles in hepatic microsomes.
Novartis Institutes for Biomedical Research , Horsham, West Sussex , UK.
Rowan A
RA
Stringer
Eckhard
E
Weber
Andrew
A
Culshaw
Jeff
J
McKenna
Gareth
G
Williams
Jonathan
J
Rose
Bindi
B
Sohal
D000818:Animals; D004285:Dogs; D022781:Hepatocytes; D006801:Humans; D008297:Male; D008862:Microsomes, Liver; D010080:Oxazoles / Q000097:blood / Q000493:pharmacokinetics*; D011720:Pyrazoles / Q000097:blood / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D000099052:CRF Receptor, Type 1
C000593013:7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-3-(4-methoxy-2-methylphenyl)-2,6-dimethylpyrazolo(5,1-b)oxazole; D010080:Oxazoles; D011720:Pyrazoles; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1
CRF1 antagonist; Clearance prediction; hepatocytes; in vitro–in vivo scaling; microsomes; pharmacokinetics