Functional evaluation of vandetanib metabolism by CYP3A4 variants and potential drug interactions in vitro

Functional evaluation of cyclosporine metabolism by CYP3A4 variants and potential drug interactions

“…Our work used CYP3A4.1 as a reference to assess the enzyme kinetic parameters of 23 other CYP3A4 variants on CsA metabolism in vitro. Depending on the relative clearance rates of CsA, we found that CYP3A4.5 and 29 had high metabolic activity, which is relatively consistent with previously published findings (Han et al, 2021a;Han et al, 2021b). As a rapidly metabolized enzyme, our data show that the relative clearance of CYP3A4.5 (603.52%) was markedly higher than that of CYP3A4.29 (163.45%), which is different from Han et al's finding that the relative clearance of CYP3A4.29 in vitro was approximately 2.8-3.6 times that of CYP3A4.5.…”

“…As a rapidly metabolized enzyme, our data show that the relative clearance of CYP3A4.5 (603.52%) was markedly higher than that of CYP3A4.29 (163.45%), which is different from Han et al's finding that the relative clearance of CYP3A4.29 in vitro was approximately 2.8-3.6 times that of CYP3A4.5. The underlying cause may be that there are wide differences in the structure of the substrates, which bind to different binding domains on CYP3A4 variants, showing metabolic differences of the same CYP3A4 variants (Zhou, 2008;Sevrioukova, 2019;Han et al, 2021b). Because the frequency distribution of the CYP3A4*5 allele is 0.5% in Han Chinese and 0.7% in Taiwan Chinese (Zhou et al, 2011;Werk and Cascorbi, 2014;Hu et al, 2017) and the population base is large, these CYP3A4*5 carriers may experience poor therapeutic effects when treated with standard therapeutic doses of CsA.…”

“…In previous studies, it has been determined that there are mutations in exon 5 of the CYP3A4.8 allele (Eiselt et al, 2001). CYP3A4.12 (21905C > T) in exon 11 results in an L373F change in the CYP3A4 protein (Lamba et al, 2002); the amino acid Leu in CYP3A4.13 replaces Pro 416; CYP3A4.14 (T44C) in exon 1 results in an L15P change; CYP3A4.16 (15612C > G ) in exon 7 results in a T185S amino acid substitution; and CYP3A4.17 produces an amino acid substitution of F189S on exon 7 (Lamba et al, 2002;Kang et al, 2009;Han et al, 2021b). These changes disrupt the structure and function of the protein, leading to decreased catalytic activity compared with the wildtype enzyme.…”

Genomewide Association Study of Simvastatin Pharmacokinetics

“…33 In vitro studies suggest that the effect of CYP3A4.2 may be substrate-specific as the clearance of some CYP3A4 substrates is reduced [34][35][36][37][38][39][40][41] whereas the clearance of others, including testosterone, 34,36,42 is unaffected or increased. 43,44 Another CYP3A4 variant, CYP3A4*22, has associated with increased plasma concentrations of simvastatin lactone and acid, and enhanced cholesterol-lowering efficacy of atorvastatin, lovastatin, and simvastatin. 11,12,45 CYP3A4*22 is an intronic variant, which alters RNA splicing and decreases CYP3A4 expression in the liver.…”

“…Studies on the effects of CYP3A4*2 on CYP3A4 activity in vivo are scarce, but one individual with the CYP3A4*2/*2 genotype was reported to have a low 6β‐OH‐cortisol/cortisol ratio indicating slow CYP3A4 metabolism 33 . In vitro studies suggest that the effect of CYP3A4.2 may be substrate‐specific as the clearance of some CYP3A4 substrates is reduced 34–41 whereas the clearance of others, including testosterone, 34,36,42 is unaffected or increased 43,44 . Another CYP3A4 variant, CYP3A4*22 , has associated with increased plasma concentrations of simvastatin lactone and acid, and enhanced cholesterol‐lowering efficacy of atorvastatin, lovastatin, and simvastatin 11,12,45 .…”