Metabolism of 3-cyanomethyl-4-methyl-DCK, a new anti-HIV candidate, in human intestinal microsomes.
- Author:
Xiao-mei ZHUANG
1
;
Yuan-yuan WEN
;
Hua LI
;
Jing-ting DENG
;
Wei-li KONG
;
Xing-tao TIAN
;
Shu-li CUI
;
Lan XIE
Author Information
1. Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China.
- Publication Type:Journal Article
- MeSH:
Anti-HIV Agents;
metabolism;
pharmacokinetics;
Biological Availability;
Bridged Bicyclo Compounds, Heterocyclic;
metabolism;
pharmacokinetics;
Coumarins;
metabolism;
pharmacokinetics;
Cytochrome P-450 CYP3A;
Cytochrome P-450 CYP3A Inhibitors;
Humans;
Intestines;
metabolism;
Ketoconazole;
pharmacology;
Metabolic Clearance Rate;
Microsomes;
metabolism;
Ritonavir;
pharmacology;
Troleandomycin;
pharmacology
- From:
Acta Pharmaceutica Sinica
2010;45(9):1116-1122
- CountryChina
- Language:Chinese
-
Abstract:
The biotransformation, CYP reaction phenotyping, the impact of CYP inhibitors and enzyme kinetics of 3-cyanomethyl-4-methyl-DCK (CMDCK), a new anti-HIV preclinical candidate belonging to DCK analogs, were investigated in human intestinal microsomes and recombinant cytochrome P450 (CYP) enzymes. CMDCK (4 micromol L(-1)) was incubated with a panel of rCYP enzymes (CYP1A2, 2C9, 2C19, 2D6 and 3A4) in vitro. The remaining parent drug in incubates was quantitatively analyzed by a LC-MS method. CYP3A4 was identified as the principal CYP isoenzyme responsible for its metabolism in intestinal microsomes. The major metabolic pathway of CMDCK was oxidation and a number of oxidative metabolites were screened with LC-MS. The Km, Vmax, CLint and T1/2 of CMDCK obtained from human intestinal microsome were 45.6 micromol L(-1), 0.33 micromol L(-1) min(-1), 12.1 mL min(-1) kg(-1) and 25.7 min, respectively. Intestinal clearance of CMDCK was estimated from in vitro data to be 3.3 mL min(-1) kg(-1), and was almost equal to the intestinal blood flow rate (4.6 mL min(-1) kg(-1)). The selective CYP3A4 inhibitors, ketoconazole, troleandomycin and ritonavir demonstrated significant inhibitory effects on CMDCK intestinal metabolism, which suggested that co-administration of CMDCK with potent CYP3A inhibitors, such as ritonavir, might decrease its intestinal metabolic clearance and subsequently improve its bioavailability in body.
