Reactome | CYP3A4, CYP2B6 bind ritonavir

CYP3A4, CYP2B6 bind ritonavir

Stable Identifier

R-HSA-9680865

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol, endoplasmic reticulum membrane

ReviewStatus

5/5

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Ritonavir binds and inhibits Cytochrome P450 3A4 (CYP3A4), the most broadly active drug metabolizing enzyme in humans. CYP3A4 oxidizes and clears over half of all administered pharmaceuticals due to its promiscuity, including antiretroviral drugs such as those used to treat HIV infection (Ernest et al. 2005). Ritonavir can thereby enhance bioavailability and prolong the plasma half life of antiretroviral drugs (Kharasch et al. 2008, Greenblatt & Harmatz 2015).

Ritonavir treatment is currently being investigated for patients with COVID-19 (many clinical trials, example registration nos. ChiCTR2000029603, ChiCTR2000029539, NCT04261270, NCT04255017) (Martinez 2020, Ortega et al. 2020, Cao et al. 2020, Deng et al. 2020, Harrison 2020). It turns out however that the best use of ritonavir is in combination with the SARS-CoV-2 nsp5 inhibitor nirmatrelvir, the combination approved and sold as Paxlovid (NCT04960202).

Literature References

PubMed ID	Title	Journal	Year
32152082	Compounds with therapeutic potential against novel respiratory 2019 coronavirus Martinez, MA	Antimicrob. Agents Chemother.	2020
25923589	Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug-drug interaction studies Greenblatt, DJ, Harmatz, JS	Br J Clin Pharmacol	2015
32210741	Unrevealing sequence and structural features of novel coronavirus using in silico approaches: The main protease as molecular target Ortega, JT, Serrano, ML, Pujol, FH, Rangel, HR	EXCLI J	2020
32205870	Coronavirus puts drug repurposing on the fast track Harrison, C	Nat. Biotechnol.	2020
15523003	Mechanism-based inactivation of CYP3A by HIV protease inhibitors Ernest, CS, Hall, SD, Jones, DR	J. Pharmacol. Exp. Ther.	2005
32171872	Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study Deng, L, Li, C, Zeng, Q, Liu, X, Li, X, Zhang, H, Hong, Z, Xia, J	J. Infect.	2020
32187464	A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 Cao, B, Wang, Y, Wen, D, Liu, W, Wang, J, Fan, G, Ruan, L, Song, B, Cai, Y, Wei, M, Li, X, Xia, J, Chen, N, Xiang, J, Yu, T, Bai, T, Xie, X, Zhang, L, Li, C, Yuan, Y, Chen, H, Li, H, Huang, H, Tu, S, Gong, F, Liu, Y, Wei, Y, Dong, C, Zhou, F, Gu, X, Xu, J, Liu, Z, Zhang, Y, Li, H, Shang, L, Wang, K, Li, K, Zhou, X, Dong, X, Qu, Z, Lu, S, Hu, X, Ruan, S, Luo, S, Wu, J, Peng, L, Cheng, F, Pan, L, Zou, J, Jia, C, Wang, J, Liu, X, Wang, S, Wu, X, Ge, Q, He, J, Zhan, H, Qiu, F, Guo, L, Huang, C, Jaki, T, Hayden, FG, Horby, PW, Zhang, D, Wang, C	N. Engl. J. Med.	2020
18285471	Rapid clinical induction of hepatic cytochrome P4502B6 activity by ritonavir Kharasch, ED, Mitchell, D, Coles, R, Blanco, R	Antimicrob. Agents Chemother.	2008