The inhibitory and inducing effects of ritonavir on hepatic and intestinal CYP3A and other drug-handling proteins

Loos, Nancy H.C.; Beijnen, Jos H.; Schinkel, Alfred H.

doi:10.1016/j.biopha.2023.114636

Cited by 14 publications

(6 citation statements)

References 55 publications

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“…The CYP3A4 inhibitor ritonavir also inhibits drug transporters P‐gp and BCRP. Therefore, a lack of clinically meaningful change in momelotinib pharmacokinetics with ritonavir may also suggest no interactions with inhibitors of these transporters 26,27 . To evaluate the effects of strong CYP3A4 induction, multiple‐dose rifampin was compared with single‐dose rifampin to remove the opposing effect of OATP1B1/1B3 inhibition by single‐dose rifampin.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, a lack of clinically meaningful change in momelotinib pharmacokinetics with ritonavir may also suggest no interactions with inhibitors of these transporters. 26 , 27 To evaluate the effects of strong CYP3A4 induction, multiple‐dose rifampin was compared with single‐dose rifampin to remove the opposing effect of OATP1B1/1B3 inhibition by single‐dose rifampin. A moderate decrease in momelotinib and increase in M21 were observed with multiple‐dose rifampin when compared with single‐dose rifampin.…”

Section: Discussionmentioning

confidence: 99%

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Clinical assessment of momelotinib drug–drug interactions via CYP3A metabolism and transporters

Ho,

Gorycki,

Ferron‐Brady

et al. 2024

Clinical Translational Sci

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Momelotinib—approved for treatment of myelofibrosis in adults with anemia—and its major active metabolite, M21, were assessed as drug–drug interaction (DDI) victims with a strong cytochrome P450 (CYP) 3A4 inhibitor (multiple‐dose ritonavir), an organic anion transporting polypeptide (OATP) 1B1/1B3 inhibitor (single‐dose rifampin), and a strong CYP3A4 inducer (multiple‐dose rifampin). Momelotinib DDI perpetrator potential (multiple‐dose) was evaluated with CYP3A4 and breast cancer resistance protein (BCRP) substrates (midazolam and rosuvastatin, respectively). DDI was assessed from changes in maximum plasma concentration (Cmax), area under the concentration–time curve (AUC), time to reach Cmax, and half‐life. The increase in momelotinib (23% Cmax, 14% AUC) or M21 (30% Cmax, 24% AUC) exposure with ritonavir coadministration was not clinically relevant. A moderate increase in momelotinib (40% Cmax, 57% AUC) and minimal change in M21 was observed with single‐dose rifampin. A moderate decrease in momelotinib (29% Cmax, 46% AUC) and increase in M21 (31% Cmax, 15% AUC) were observed with multiple‐dose rifampin compared with single‐dose rifampin. Due to potentially counteracting effects of OATP1B1/1B3 inhibition and CYP3A4 induction, multiple‐dose rifampin did not significantly change momelotinib pharmacokinetics compared with momelotinib alone (Cmax no change, 15% AUC decrease). Momelotinib did not alter the pharmacokinetics of midazolam (8% Cmax, 16% AUC decreases) or 1′‐hydroxymidazolam (14% Cmax, 16% AUC decreases) but increased rosuvastatin Cmax by 220% and AUC by 170%. Safety findings were mild in this short‐term study in healthy volunteers. This analysis suggests that momelotinib interactions with OATP1B1/1B3 inhibitors and BCRP substrates may warrant monitoring for adverse reactions or dose adjustments.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Clinical assessment of momelotinib drug–drug interactions via CYP3A metabolism and transporters

Ho,

Gorycki,

Ferron‐Brady

et al. 2024

Clinical Translational Sci

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“…dQ: amount of transporter test drug in pmol; dT: incubation time in seconds; A: surface of porous membrane in cm 2 (standard: 0.7); C 0 : initial concentration of test agent in the donor chamber in pmol/cm 3 .…”

Section: Caco-2 Substrate Assessment Of Docetaxel and Bidirectional P...mentioning

confidence: 99%

“…The standard of care treatment with docetaxel for mCRPC patients is intravenous administration of 75 mg/m 2 once every 3 weeks. A common problem with docetaxel treatment is failure attributed to the development of resistance, possibly due to increased efflux from the site of action caused by P-glycoprotein (P-gp) [3] . Ritonavir is an HIV protease inhibitor originally used for the treatment of HIV patients, and is now also commonly used as a "booster" of other drugs [4] (most recently in combination with nirmatrelvir for the treatment of COVID-19) due to its ability to inhibit both cytochrome P4503A4 (CYP3A4) [5] and P-gp [6] .…”

Section: Introductionmentioning

confidence: 99%

Ritonavir reverses resistance to docetaxel and cabazitaxel in prostate cancer cells with acquired resistance to docetaxel

van der Putten,

Wosikowski,

Beijnen

et al. 2024

Cancer Drug Resist

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Aim: Docetaxel is a microtubule-stabilizing drug used for the treatment of several cancers, including prostate cancer. Resistance to docetaxel can either occur through intrinsic resistance or develop under therapeutic pressure, i.e., acquired resistance. A possible explanation for the occurrence of acquired resistance to docetaxel is increased drug efflux via P-glycoprotein (P-gp) drug transporters. Methods: We have generated docetaxel-resistant cell lines DU-145DOC10 and 22Rv1DOC8 by exposing parental cell lines DU-145DOC and 22Rv1 to increasing levels of docetaxel. Gene expression levels between DU-145DOC10 and 22Rv1DOC8 were compared with those of their respective originator cell lines. Both parental and resistant cell lines were treated with the taxane drugs docetaxel and cabazitaxel in combination with the P-gp/CYP3A4 inhibitor ritonavir and the P-gp inhibitor elacridar. Results: In the docetaxel-resistant cell lines DU-145DOC10 and 22Rv1DOC8, the ABCB1 (P-gp) gene was highly up-regulated. Expression of the P-gp protein was also significantly increased in the docetaxel-resistant cell lines in a Western blotting assay. The addition of ritonavir to docetaxel resulted in a return of the sensitivity to docetaxel in the DU-145DOC10 and 22Rv1DOC8 to a level similar to the sensitivity in the originator cells. We found that these docetaxel-resistant cell lines could also be re-sensitized to cabazitaxel in a similar manner. In a Caco-2 P-gp transporter assay, functional inhibition of P-gp-mediated transport of docetaxel with ritonavir was demonstrated. Conclusion: Our results demonstrate that ritonavir restores sensitivity to both docetaxel and cabazitaxel in docetaxel-resistant cell lines, most likely by inhibiting P-gp-mediated drug efflux.

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“…Ritonavir is one of the first prescribed HIV-protease inhibitors and was approved by the FDA in 1996 [ 46 , 47 ]. Ritonavir is nowadays used primarily to increase the bioavailability of other HIV drugs as it inhibits their major metabolising enzyme, P450 3A4 monooxygenase [ 48 , 49 ]. For the latter reason, ritonavir is used in combination with the COVID-19 protease inhibitor nirmatrelvir as part of the new therapeutic drug paxlovid, which has been shown to drastically reduce the risk of severe disease progression after infection with COVID-19 [ 50 , 51 ].…”

Section: Introductionmentioning

confidence: 99%

Modulation of Multidrug Resistance Protein 1-mediated Transport Processes by the Antiviral Drug Ritonavir in Cultured Primary Astrocytes

Arend,

Grothaus,

Waespy

et al. 2023

Neurochem Res

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The Multidrug Resistance Protein 1 (Mrp1) is an ATP-dependent efflux transporter and a major facilitator of drug resistance in mammalian cells during cancer and HIV therapy. In brain, Mrp1-mediated GSH export from astrocytes is the first step in the supply of GSH precursors to neurons. To reveal potential mechanisms underlying the drug-induced modulation of Mrp1-mediated transport processes, we investigated the effects of the antiviral drug ritonavir on cultured rat primary astrocytes. Ritonavir strongly stimulated the Mrp1-mediated export of glutathione (GSH) by decreasing the Km value from 200 nmol/mg to 28 nmol/mg. In contrast, ritonavir decreased the export of the other Mrp1 substrates glutathione disulfide (GSSG) and bimane-glutathione. To give explanation for these apparently contradictory observations, we performed in silico docking analysis and molecular dynamics simulations using a homology model of rat Mrp1 to predict the binding modes of ritonavir, GSH and GSSG to Mrp1. The results suggest that ritonavir binds to the hydrophilic part of the bipartite binding site of Mrp1 and thereby differently affects the binding and transport of the Mrp1 substrates. These new insights into the modulation of Mrp1-mediated export processes by ritonavir provide a new model to better understand GSH-dependent detoxification processes in brain cells.

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The inhibitory and inducing effects of ritonavir on hepatic and intestinal CYP3A and other drug-handling proteins

Cited by 14 publications

References 55 publications

Clinical assessment of momelotinib drug–drug interactions via CYP3A metabolism and transporters

Clinical assessment of momelotinib drug–drug interactions via CYP3A metabolism and transporters

Ritonavir reverses resistance to docetaxel and cabazitaxel in prostate cancer cells with acquired resistance to docetaxel

Modulation of Multidrug Resistance Protein 1-mediated Transport Processes by the Antiviral Drug Ritonavir in Cultured Primary Astrocytes

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