Ticagrelor is the first reversible, direct-acting, potent P2Y12 receptor antagonist in management of acute coronary syndromes. It is rapidly absorbed and extensively metabolized. AR-C124910XX, the major active metabolite, antagonizes the P2Y12 receptor at approximately equal potency. The metabolism of ticagrelor to AR-C124910XX involves CYP3A4 and CYP3A5. CYP3A polymorphisms have been well docu...

Cytochrome P450 3A4 (CYP3A4) is the most plentiful cytochrome P450 in adult human liver and small intestine and is responsible for detoxification of more than 50% of drugs in addition to the metabolic deactivation and metabolism of many carcinogens. Polymorphism of CYP3A4-A-290G considered the only allele that appears to stimulate CYP3A4 expression and has been associated with a number of clini...

The objective of this study was to identify CYP3A4 variants in Koreans and to characterize their functional consequences in vitro and in vivo. Four single nucleotide polymorphisms were identified in 50 Koreans by direct DNA sequencing. In an additional genotyping using 248 subjects, CYP3A4(*)18 was confirmed as the most frequent coding variant in Koreans at 1.7%, and its frequency was similar t...

Recent data suggest that the role of CYP3A4 in imatinib metabolism is smaller than presumed. This study aimed to evaluate the quantitative importance of different cytochrome P450 (P450) enzymes in imatinib pharmacokinetics. First, the metabolism of imatinib was investigated using recombinant P450 enzymes and human liver microsomes with P450 isoform-selective inhibitors. Thereafter, an in silico...

Farnesoid X receptor (FXR) functions as a regulator of bile acid and lipid homeostasis and is recognized as a promising therapeutic target for metabolic diseases. The biologic function of FXR is mediated in part by a small heterodimer partner (SHP); ligandactivated FXR enhances SHP expression, and SHP in turn represses the activity of multiple transcription factors. This study aimed to investig...

Drug-drug interactions (DDIs) via cytochrome P450 (P450) induction are one clinical problem leading to increased risk of adverse effects and the need for dosage adjustments and additional therapeutic monitoring. In silico models for predicting P450 induction are useful for avoiding DDI risk. In this study, we have established regression models for CYP3A4 and CYP2B6 induction in human hepatocyte...

Some compounds used for phenotyping of cytochrome P450s are substrates of P-glycoprotein (pgp). It is likely that in these cases, the level of pgp modulates the metabolism of in vivo probes. To address this important issue, we have analyzed the effects of pgp on CYP3A4-mediated reactions in two newly established cell lines (3A4/HR/MDR(-) and 3A4/HR/MDR(+)), which express CYP3A4 in the absence a...

Since CYP3A4 is responsible for the biotransformation of over 50% of all clinically used drugs, induction results in an increased clearance of many concomitantly administered drugs, thereby decreasing treatment efficacy or, in the case of prodrugs, lead to severe intoxications. CYP3A4 induction is regulated by the pregnane X receptor, constitutive androstane receptor, and vitamin D receptor. Si...

Cytochrome P-450 3A4 (CYP3A4) contributes to the metabolism of approximately half the drugs in clinical use today. The aim of the present study was to determine the frequency of the CYP3A4*1B, *2, *4, *5, and *18 alleles amongst both Tepehuan Amerindians, a native group that has inhabited northern Mexico for thousands of years, and Mestizo Mexicans, and to compare the data with those of other p...

CYP3A4, an isoform of cytochrome P450 enzymes, is responsible for the metabolism of 45% to 60% of currently prescribed drugs. It has been shown that CYP3A4*1G, a single nucleotide polymorphism (SNP), affects the enzymatic activity of CYP3A4. Sufentanil, a synthetic opioid commonly used for the induction and maintenance of general anesthesia, analgesia, and sedation, is mainly metabolized by CYP...