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Preclinical metabolism and pharmacokinetics of NVS-CRF38, a potent and orally bioavailable corticotrophin-releasing factor-1 antagonist

Stringer, Rowan and Weber, Eckhard and Culshaw, Andrew and Mckenna, Jeff and Williams, Gareth and Rose, Jonathan and Sohal, Bindi (2014) Preclinical metabolism and pharmacokinetics of NVS-CRF38, a potent and orally bioavailable corticotrophin-releasing factor-1 antagonist. Xenobiotica, 44 (10). pp. 902-912. ISSN 0049-8254

Abstract

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] 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 hepatic microsomes and cryopreserved hepatocytes 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 suicide inhibitor 1-aminobenzotriazole, implicating cytochrome P450 enzymes in the primary metabolism of this compound.
5. NVS-CRF38 is weakly bound to blood 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 rats 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.

Item Type: Article
Keywords: Microsomes, hepatocytes, clearance prediction, in vitro-in vivo scaling, CRF1 antagonist, pharmacokinetics
Date Deposited: 13 Jan 2016 00:45
Last Modified: 13 Jan 2016 00:45
URI: https://oak.novartis.com/id/eprint/9368

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