Different effects of dihydropyridine calcium channel antagonists on CYP3A4 enzyme of human liver microsomes

Abstract

The present study investigated inhibitory effects of 1,4-dihydropyridines (1,4-DHPs) calcium channel antagonists (1,4-DHP-CCAs) on cytochromeP450 3A4 (CYP3A4) of human liver microsomes and further explored importance of 1,4-DHPs molecular structural descriptors. Partial Least Squares method was applied to probe the quantitative relationships between the 1,4-DHPs molecular structural descriptors and its inhibitory actions, which demonstrated that different 1,4-DHP-CCAs could inhibit CYP3A4 enzyme's activity differently. The K (i) values of nicardipine, lercandipine, cilnidipine, nitrendipine, lacidipine, nifedipine, felodipine were 10.13, 10.17, 11.44, 23.90, 29.34, 29.06 and 32.64 μmol L⁻¹, respectively. It is suggested that the 1,4-DHPs molecular structural descriptors are the most important for its inhibitory effects based on the quantitative structure-activity relationship (QSAR) formula. The LogP was positively correlated to the K (i), whereas molecular weight and molecule volume were negatively correlated. It is concluded that analysis of K (i) of 1,4-DHPs derivatives on the CYP3A4 activity may apply for the QSAR formula at the initial stage of clinical application of new drugs.

Pharmacokinetic Drug-Drug Interaction of Calcium Channel Blockers With Cyclosporine in Hematopoietic Stem Cell Transplant Children

“…Our results suggest the lack of pharmacokinetic interaction between lacidipine and CsA. This is in agreement with in vitro results from Xia et al 13 who measured a relatively high CYP3A4 inhibition constant (Ki) for lacidipine, suggesting little or no inhibition potency. This analysis has several limitations that should be considered, including (1) the uncontrolled, retrospective design; (2) lack of patients' full pharmacokinetic profile of CsA; and (3) the limited sample size.…”

“…Target TBC was set at 120 to 150 ng/mL in patients without GVHD and 150 to 200 ng/mL in case of GVHD occurrence, depending on GVHD severity. 13 Outcome Because of those individual changes of CsA dose over the study period, we did not examine actual CsA trough concentrations but dose-normalized trough concentrations, expressed by the ratio of CsA TBC (in ng/mL) over CsA daily dose (in mg/kg). Daily doses were expressed per kilogram of actual body weight, which may also have changed a little over the study period for some patients.…”

“…Target TBC was set at 120 to 150 ng/mL in patients without GVHD and 150 to 200 ng/mL in case of GVHD occurrence, depending on GVHD severity. 13…”

“…[7][8][9][10] CCBs are metabolized by cytochrome P450 3A4 enzymes (CYP3A4) and also have an inhibitory effect on CYP3A4, which varies from one agent to another. [11][12][13] Inhibition of CYP3A4 by CCBs may lead to a reduced clearance of coadministered drugs also metabolized by CYP3A4 such as CsA, which is commonly used to prevent graft-versus-host disease (GVHD) in HSCT. Indeed, CsA is mainly metabolized by liver and intestinal CYP3A4 and is also a P-glycoprotein substrate.…”

“…14 Among the available CCBs, nicardipine has been shown to have the strongest inhibition potential on CYP3A4, followed by lercanidipine, cilnidipine, nimodipine, and amlodipine. 13 Among the weakest CYP3A4 inhibitors, lacidipine is the only one available in France (not in the United States) as a suitable formulation for pediatric use (tablets with immediate release can be crushed to prepare low-dosage capsules). 13…”