Nevirapine
M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson in Kucers’ The Use of Antibiotics, 2017
Many drug interactions occur at the level of different cytochrome P-450 isoenzymes. Nevirapine is both a substrate for and induces cytochrome P-4503A4 and 2B6 enzymes (Back et al., 2003) but has no significant effect on cytochrome P-4501A2, 2D6, 2C9, or 2C19 enzymes (von Moltke et al., 2001). CYP3A4 is present in gastrointestinal enterocytes as well as at the primary site, the liver. In addition, modification of activity and expression of active drug transport systems by nevirapine are both important in determining the pharmacokinetics of nevirapine. P-glycoprotein is not involved in nevirapine transport (Stormer et al., 2002) and nevirapine does not induce P-glycoprotein expression (Chandler et al., 2003). Multidrug resistance–related proteins (MRPs) also contribute to elimination of drugs and their metabolites as efflux transporters. Nevirapine is a weak inhibitor of MRP1, MRP2, and MRP3, and a modest inhibitor of the breast cancer resistance protein (BCRP/ABCG2), the clinical relevance of which has not been determined in clinical studies (Weiss et al., 2007a; Weiss et al., 2007b).
Introduction to Human Cytochrome P450 Superfamily
Shufeng Zhou in Cytochrome P450 2D6, 2018
The CYP3A4 gene is located on chromosome 7q22.1 and is approximately 27 kb long consisting of 13 exons and 12 introns (Brooks et al. 1988). CYP3A4 is the most abundant CYP in human liver, accounting for 25%–30% total CYPs, and in the small intestine. The enzyme is also present in the lung, stomach, colon, and adrenal gland but not in the kidney, prostate, testis, or thymus. The enzyme has a dominant role in drug metabolism. There is a large intraindividual variation in CYP3A4 gene expression as much as 10-folds (Haddad et al. 2007) and up to 90-fold in CYP3A4 protein expression in liver samples (Schuetz 2004). CYP3A4 varies with gender, with 25% higher enzymatic activity in females (Hunt et al. 1992; Wolbold et al. 2003). There is no significant difference with age (Haddad et al. 2007). The level of CYP3A4 is low in fetal liver, although the expression rapidly increases after birth and reaches 50% of adult levels between 6 and 12 months of age.
Paediatric clinical pharmacology
Evelyne Jacqz-Aigrain, Imti Choonara in Paediatric Clinical Pharmacology, 2021
The CYP3A4 enzyme is the predominant form in adults, identified both in the liver and the gut [17]. It is variably expressed [16,18,19], but none of the identified genetic polymorphisms seem to have any functional correlate. CYP3 A4 enzymes are important for the metabolism of a large number of commonly used drugs within the groups of antiepileptics, immunosuppressants, cytotoxics, antibiotics etc. As the enzyme is frequently subject to induction and inhibition, there are possible clinical implications [20]. CYP3A5 is also present in the liver, but is predominantly an extrahepatic form of the CYP3A enzymes. CYP3A5 mRNA is present in the intestine and can be detected using sensitive methods such as real time quantitative RT-PCR [21,22]. The variability of CYP3A5 expression is under genetic control. Individuals with two CYP3A5*1 alleles have high expression and up to 10 fold increase in CYP3A5 protein. This is observed in 10 to 30% of livers in Caucasians [23,24]. The contribution of CYP3A5 to drug metabolism is important, as CYP3A5 when it is expressed can contribute to over 50% of the total CYP3A content.
Baicalein inhibits the pharmacokinetics of simvastatin in rats via regulating the activity of CYP3A4
Published in Pharmaceutical Biology, 2021
Meng Meng, Xin Li, Xiuwen Zhang, Bin Sun
Baicalein was found to change the pharmacokinetic profile of simvastatin and increase the AUC of simvastatin and prolonged the t1/2 in rats, indicating the increasing system exposure of simvastatin. CYP3A4 is one of the major isoforms of cytochrome P450 enzymes, which is responsible for first-pass metabolism and bioavailability of numerous drugs and herbs (Manikandan and Nagini 2018). The effect of different drugs on the activity of CYP3A4 could induce adverse drug–drug interactions that are closely associated with the drug biotransformation and therapeutic efficiency (Zhou 2008). In a previous study, baicalein was reported to inhibit the clearance of tamoxifen by inhibiting CYP3A4 and P-gp and therefore increase the drug bioavailability (Li, Kim, et al. 2011). Here, the inhibitory effect of baicalein on the activity of CYP3A4 was also validated in rat liver microsomes. It was found that baicalein dramatically inhibited the activity of CYP3A4 in a dose-dependent manner with the specific IC50 value. It has been demonstrated that simvastatin is highly selective to the liver, where its concentration is significantly higher than in other tissues (Pedersen and Tobert 2004). CYP3A4 is widely distributed in the liver and contributes to the metabolism of simvastatin (Kitzmiller et al. 2014). Hence, it was speculated that the effect of baicalein on the pharmacokinetics of simvastatin was a result of the inhibition of CYP3A4.
Insights into oral bioavailability enhancement of therapeutic herbal constituents by cytochrome P450 3A inhibition
Published in Drug Metabolism Reviews, 2021
Junmei Chen, Jinman Liu, Yueyue Huang, Ruoyu Li, Cuiru Ma, Beiping Zhang, Fanchang Wu, Wenqian Yu, Xue Zuo, Yong Liang, Qi Wang
CYP3A is the most abundant CYP isoforms in the liver, accounting for about 30% of the total amount of CYP enzymes (Lin and Lu 2001). Due to the low blood flow of intestinal mucosa and the prolonged exposure to enzymes (Miron et al. 2017), CYP3A in the intestine probably plays an important role, consistent with its effects on the liver structure and function (Lin and Lu 2001). The activity and content of CYP3A are increased slightly from the duodenum to the middle jejunum and then decreased from the distal jejunum to the ileum (Paine et al. 1997). Although considerable heterogeneities of CYP3A subfamily expression are observed in the liver and intestine (Gellner et al. 2001), CYP3A4 is still recognized as the primary CYP isoenzyme abundantly expressed in the liver and small intestine of human adults (Lamba et al. 2002). CYP3A4 and CYP3A5 constitute the main hepatic P450 enzymes, and the average specific content accounts for 29% of the P450 content determined by the spectrum (Shimada et al. 1994). On the other hand, CYP3A4 accounts for 80% of the total enzyme in the intestine (Paine et al. 2006). CYP3A5 exists in the liver and intestine of adults, while its expression is polymorphic, exhibiting a relatively higher or lower protein level in different individuals (Wrighton et al. 1990; Paine et al. 1997). CYP3A7 is mainly found in the fetal liver and is detected in the adult liver (de Wildt et al. 1999; Tateishi et al. 1999). Although CYP3A43 localizes in the liver, kidney, prostate, and pancreas, it is not considered a major contributor to drug clearance due to its lower expression level (Lamba et al. 2002).
Cannabidiol drug interaction considerations for prescribers and pharmacists
Published in Expert Review of Clinical Pharmacology, 2022
Myfanwy Graham, Jennifer H Martin, Catherine J Lucas, Bridin Murnion, Jennifer Schneider
Many commonly prescribed drugs are metabolized by the CYP enzymes and may be candidates for drug–drug interactions with cannabidiol. For example, CYP3A4 is involved in the metabolism of about a quarter of all commonly used drugs and inhibition of CYP3A4 may increase serum concentrations of macrolides, calcium channel blockers, benzodiazepines, cyclosporine, sildafenil, antihistamines, haloperidol, antiretrovirals, and some statins. CYP2D6 metabolizes many antidepressants and inhibition has the potential to increase serum concentrations of selective serotonin reuptake inhibitors, tricyclic antidepressants, antipsychotics, beta-blockers, and opioids such as codeine and oxycodone [27]. Some standard drug interaction checking platforms do not distinguish between minor and major CYP metabolic pathways and clinical significance data is not readily available for many potential cannabidiol interactions.
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