Dmd #13847 1 Sequential Metabolism Is Responsible for Diltiazem Induced Time-dependent Loss of Cyp3a
نویسندگان
چکیده
248
منابع مشابه
Sequential metabolism is responsible for diltiazem-induced time-dependent loss of CYP3A.
Kinetic parameters (k(inact) and K(I)) obtained in microsomes are often used to predict time-dependent inactivation. We previously reported that microsomal inactivation kinetic parameters of diltiazem underpredicted CYP3A inactivation in hepatocytes. In this study, we evaluated the contributions of inactivation and reversible inhibition of CYP3A by diltiazem and its N-desmethyl (MA) and N,N-did...
متن کاملAn inhibitory metabolite leads to dose- and time-dependent pharmacokinetics of (R)-N-{1-[3-(4-ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl}-N-pyridin-3-yl-methyl-2-(4-trifluoromethoxy-phenyl)-acetamide (AMG 487) in human subjects after multiple dosing.
(R)-N-{1-[3-(4-Ethoxy-phenyl)-4-oxo-3,4-dihydro-pyrido[2,3-d]-pyrimidin-2-yl]-ethyl}-N-pyridin-3-yl-methyl-2-(4-trifluoromethoxyphenyl)-acetamide (AMG 487) is a potent and selective orally bioavailable chemokine (C-X-C motif) receptor 3 (CXCR3) antagonist that displays dose- and time-dependent pharmacokinetics in human subjects after multiple oral dosing. Although AMG 487 exhibited linear pharm...
متن کاملEvaluation of time-dependent inactivation of CYP3A in cryopreserved human hepatocytes.
Irreversible CYP3A inhibition by drugs constitutes one of the major causes of inhibition-based drug interactions. We evaluated time-dependent inactivation of CYP3A in cryopreserved human hepatocytes for six structurally diverse compounds known to exhibit this property. Inactivation kinetic parameters were also determined using human liver microsomes. Except for diclofenac, which did not cause C...
متن کاملHydroxyitraconazole, formed during intestinal first-pass metabolism of itraconazole, controls the time course of hepatic CYP3A inhibition and the bioavailability of itraconazole in rats.
Itraconazole (ITZ) is a substrate of CYP3A and both ITZ and hydroxyitraconazole (OH-ITZ), a major metabolite formed by CYP3A, are potent inhibitors of CYP3A. The concentration- and time-dependent changes in the hepatic availability (F(H)) of ITZ were evaluated in rats after oral doses of 5 and 40 mg/kg. Simultaneous blood samples were obtained from the aorta, portal vein, and hepatic vein for 2...
متن کاملDrug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A.
The inhibitory effects of six commonly used calcium channel blockers on three major cytochrome P-450 activities were examined and characterized in human liver microsomes. All six compounds reversibly inhibited CYP2D6 (bufuralol 1'-hydroxylation) and CYP2C9 (tolbutamide methyl hydroxylation) activities. The IC(50) values for the inhibition of CYP2D6 and CYP2C9 for nicardipine were 3 to 9 microM,...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
دوره شماره
صفحات -
تاریخ انتشار 2007