Quantitative analysis of pharmacokinetic profiles of verapamil and drug–drug interactions induced by a CYP inhibitor using a stable isotope-labeled compound

Quantitative Analysis of the Transporter-Mediated Drug-Drug Interaction Between Atorvastatin and Rifampicin Using a Stable Isotope-IV Method

“…The treatment and analytical procedures of plasma samples were performed with a similar method previously reported. 5 Briefly, all plasma samples (0.1 mL) were deproteinized with acetonitrile (0.9 mL) and then centrifuged. The solvent of the supernatant (0.8 mL) was evaporated and then the residue was dissolved in 0.1 mL of the solution consisting of 0.1% (vol/vol) formic acid and acetonitrile (50/50).…”

“…For the study with mouse or rats, only 2 groups, control and DDI-induced groups, are required as was demonstrated in this report and in our previous one. 5 In the previous report, the isotope-IV method was used to analyze the effect of CYP inhibition on the plasma profile of orally administered verapamil. Deuterium-labeled verapamil with 6 substituted deuterium in the molecule was used as a stable isotope of verapamil and was intravenously administered to rats pretreated with 1-aminobenzotriazole, a potent CYP inhibitor.…”

“…In the previous report, we have proposed a novel approach for analyzing the mechanism and the extent of DDIs caused by the inhibition of drug metabolizing enzymes in the liver. 5 In that study, small amount of deuterium-labeled verapamil (VER-d6) was intravenously injected to rats following the oral administration of verapamil hydrochloride (VER) with or without a pretreatment with 1-aminobenzotriazole, a potent CYP inhibitor. By assuming that VER-d6 shows the same pharmacokinetic properties with those of VER, the PK parameters of VER such as AUC po , AUC iv , F oral , and CL tot could be calculated from the same rat in a single experiment.…”