The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism?
Ritonavir is the most potent cytochrome P450 (CYP) 3A4 inhibitor in clinical use and is often applied as a booster for drugs with low oral bioavailability due to CYP3A4-mediated biotransformation, as in the treatment of HIV (e.g., lopinavir/ritonavir) and more recently COVID-19 (Paxlovid or nirmatre...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/17/9866 |
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| author | Nancy H. C. Loos Jos H. Beijnen Alfred H. Schinkel |
| author_facet | Nancy H. C. Loos Jos H. Beijnen Alfred H. Schinkel |
| author_sort | Nancy H. C. Loos |
| collection | DOAJ |
| description | Ritonavir is the most potent cytochrome P450 (CYP) 3A4 inhibitor in clinical use and is often applied as a booster for drugs with low oral bioavailability due to CYP3A4-mediated biotransformation, as in the treatment of HIV (e.g., lopinavir/ritonavir) and more recently COVID-19 (Paxlovid or nirmatrelvir/ritonavir). Despite its clinical importance, the exact mechanism of ritonavir-mediated CYP3A4 inactivation is still not fully understood. Nonetheless, ritonavir is clearly a potent mechanism-based inactivator, which irreversibly blocks CYP3A4. Here, we discuss four fundamentally different mechanisms proposed for this irreversible inactivation/inhibition, namely the (I) formation of a metabolic-intermediate complex (MIC), tightly coordinating to the heme group; (II) strong ligation of unmodified ritonavir to the heme iron; (III) heme destruction; and (IV) covalent attachment of a reactive ritonavir intermediate to the CYP3A4 apoprotein. Ritonavir further appears to inactivate CYP3A4 and CYP3A5 with similar potency, which is important since ritonavir is applied in patients of all ethnicities. Although it is currently not possible to conclude what the primary mechanism of action in vivo is, it is unlikely that any of the proposed mechanisms are fundamentally wrong. We, therefore, propose that ritonavir markedly inactivates CYP3A through a mixed set of mechanisms. This functional redundancy may well contribute to its overall inhibitory efficacy. |
| first_indexed | 2024-03-10T01:44:41Z |
| format | Article |
| id | doaj.art-d67764d300e34001b956a2786d9b02e6 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:44:41Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d67764d300e34001b956a2786d9b02e62023-11-23T13:18:26ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012317986610.3390/ijms23179866The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism?Nancy H. C. Loos0Jos H. Beijnen1Alfred H. Schinkel2The Netherlands Cancer Institute, Division of Pharmacology, 1066 CX Amsterdam, The NetherlandsFaculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, 3584 CS Utrecht, The NetherlandsThe Netherlands Cancer Institute, Division of Pharmacology, 1066 CX Amsterdam, The NetherlandsRitonavir is the most potent cytochrome P450 (CYP) 3A4 inhibitor in clinical use and is often applied as a booster for drugs with low oral bioavailability due to CYP3A4-mediated biotransformation, as in the treatment of HIV (e.g., lopinavir/ritonavir) and more recently COVID-19 (Paxlovid or nirmatrelvir/ritonavir). Despite its clinical importance, the exact mechanism of ritonavir-mediated CYP3A4 inactivation is still not fully understood. Nonetheless, ritonavir is clearly a potent mechanism-based inactivator, which irreversibly blocks CYP3A4. Here, we discuss four fundamentally different mechanisms proposed for this irreversible inactivation/inhibition, namely the (I) formation of a metabolic-intermediate complex (MIC), tightly coordinating to the heme group; (II) strong ligation of unmodified ritonavir to the heme iron; (III) heme destruction; and (IV) covalent attachment of a reactive ritonavir intermediate to the CYP3A4 apoprotein. Ritonavir further appears to inactivate CYP3A4 and CYP3A5 with similar potency, which is important since ritonavir is applied in patients of all ethnicities. Although it is currently not possible to conclude what the primary mechanism of action in vivo is, it is unlikely that any of the proposed mechanisms are fundamentally wrong. We, therefore, propose that ritonavir markedly inactivates CYP3A through a mixed set of mechanisms. This functional redundancy may well contribute to its overall inhibitory efficacy.https://www.mdpi.com/1422-0067/23/17/9866ritonavirCYP3Amechanism of actionmechanism-based inhibitor/inactivator |
| spellingShingle | Nancy H. C. Loos Jos H. Beijnen Alfred H. Schinkel The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism? International Journal of Molecular Sciences ritonavir CYP3A mechanism of action mechanism-based inhibitor/inactivator |
| title | The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism? |
| title_full | The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism? |
| title_fullStr | The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism? |
| title_full_unstemmed | The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism? |
| title_short | The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism? |
| title_sort | mechanism based inactivation of cyp3a4 by ritonavir what mechanism |
| topic | ritonavir CYP3A mechanism of action mechanism-based inhibitor/inactivator |
| url | https://www.mdpi.com/1422-0067/23/17/9866 |
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