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Introduction to Human Cytochrome P450 Superfamily
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
The substrate specificity of the CYP3A4 enzymes is very broad, with an extremely large number of structurally divergent chemicals being metabolized often in a regio- and stereoselective fashion (Sevrioukova and Poulos 2013d; Thummel and Wilkinson 1998; Zhou 2008a). CYP3A4 is known to metabolize a large variety of compounds varying in molecular weight from lidocaine (Mr = 234 Da) to cyclosporine (Mr = 1203 Da). CYP3A4 exhibits a relatively large substrate-binding cavity that is consistent with its capacity to oxidize bulky substrates such as cyclosporine, statins, taxanes, and macrolide antibiotics. Although the active-site volume is similar to that of CYP2C8, the shape of the activesite cavity differs considerably because of differences in the folding and packing of portions of the protein that form the cavity. Compared with CYP2C8, the active-site cavity of 3A4 is much larger near the heme iron (Yano et al. 2004). A small number of drugs are used as model substrates of CYP3A4 when assessing in vitro and in vivo phenotyping activity and drug interactions. Testosterone is the most commonly used in vitro CYP3A4 probe (50% of reported studies) in contrast to midazolam (15%–20% of in vitro estimates of CYP3A4 activity), whereas nifedipine, felodipine, and erythromycin are used in <10% of studies (Yuan et al. 2002). In vivo CYP3A4 function can be determined noninvasively by the erythromycin breath test (Chiou et al. 2001). Midazolam is considered as one of the best in vivo probe drugs for the study of CYP3A4 activity. A considerable number, but not all (e.g., benzodiazepines), of CYP3A substrates interact with P-gp either as substrates or as inhibitors (calcium channel blockers, azole antifungal agents, immunosuppressants, natural product anticancer agents, and macrolide antibiotics). CYP3A4 catalyzes 6a-hydroxylation of the hepatotoxic lithocholic acid and 25-hydroxylation of the cholic acid precursor 5β-cholestane-3α,7α,12α-triol (Araya and Wikvall 1999; Bodin et al. 2005). These substrates of CYP3A4 are ligands for PXR. Oxysterol 4β-hydroxycholesterol is formed by CYP3A4, and this oxysterol has been used as a marker reaction for determining CYP3A4/5 activity (Diczfalusy et al. 2009; A. Honda et al. 2011).
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
The effect of CYP3A4 inhibition on cannabidiol kinetics was investigated in rats administered ketoconazole. The AUC for lower dose cannabidiol was increased by ketoconazole, but not the AUC for higher dose suggesting saturable metabolism. In this study, cannabidiol at higher doses of 10 and 50 mg/kg but not 1 mg/kg inhibited CYP3A4 demonstrated with the erythromycin breath test. Cmax corresponding to the 1, 10 and 50 mg/kg cannabidiol doses were 0.12 μM, 1.23 μM and 11.4 μM, respectively [69].