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.
Subject(s)
Humans , 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 , Intestines , Metabolism , Ketoconazole , Pharmacology , Metabolic Clearance Rate , Microsomes , Metabolism , Ritonavir , Pharmacology , Troleandomycin , PharmacologyABSTRACT
As one of the risk factors for atherosclerosis,human cytomegalovirus infection has received increasing attention,while cytomegalovirus infection of vascular endothelial cells is considered as the initial stage of causing atherosclerosis.Therefore,elucidating the mechanism of human cytomegalovirus infection of vascular endothelial cells will help further confirm the viral and etiological theories of atherosclerosis,and may block its occurrence and development from the initial stage of infection.