title: [Metabolism of 3-cyanomethyl-4-methyl-DCK, a new anti-HIV candidate, in human intestinal microsomes].
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.
authors.affiliation: Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China.
authors.forename: Xiao-mei
authors.initials: XM
authors.lastname: Zhuang
authors.forename: Yuan-yuan
authors.initials: YY
authors.lastname: Wen
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Jing-ting
authors.initials: JT
authors.lastname: Deng
authors.forename: Wei-li
authors.initials: WL
authors.lastname: Kong
authors.forename: Xing-tao
authors.initials: XT
authors.lastname: Tian
authors.forename: Shu-li
authors.initials: SL
authors.lastname: Cui
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
mesh_terms: D019380:Anti-HIV Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D001682:Biological Availability; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism* / Q000493:pharmacokinetics; D003374:Coumarins / Q000378:metabolism* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007654:Ketoconazole / Q000494:pharmacology; D008657:Metabolic Clearance Rate; D008861:Microsomes / Q000378:metabolism*; D019438:Ritonavir / Q000494:pharmacology; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: C534490:3-cyanomethyl-4-methyl-3',4'-di-O-camphanoylkhellactone; D019380:Anti-HIV Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003374:Coumarins; D065692:Cytochrome P-450 CYP3A Inhibitors; D014217:Troleandomycin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D019438:Ritonavir; D007654:Ketoconazole