Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI27WDBTQ)
Drug Name			Ritonavir		Drug Info		Rifabutin		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Anti-Hiv Agents				Antibiotics
Structure

Mechanism of Ritonavir-Rifabutin Interaction (Severity Level: Major)
CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph

Drug Name		Ritonavir				Rifabutin
Mechanism		CYP450 3A4 inhibitor				CYP450 3A4 substrate
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 3A4				× Structure Sequence MALIPDLAMETWLLLAVSLVLLYLYGTHSHGLFKKLGIPGPTPLPFLGNILSYHKGFCMFDMECHKKYGKVWGFYDGQQPVLAITDPDMIKTVLVKECYSVFTNRRPFGPVGFMKSAISIAEDEEWKRLRSLLSPTFTSGKLKEMVPIIAQYGDVLVRNLRREAETGKPVTLKDVFGAYSMDVITSTSFGVNIDSLNNPQDPFVENTKKLLRFDFLDPFFLSITVFPFLIPILEVLNICVFPREVTNFLRKSVKRMKESRLEDTQKHRVDFLQLMIDSQNSKETESHKALSDLELVAQSIIFIFAGYETTSSVLSFIMYELATHPDVQQKLQEEIDAVLPNKAPPTYDTVLQMEYLDMVVNETLRLFPIAMRLERVCKKDVEINGMFIPKGVVVMIPSYALHRDPKYWTEPEKFLPERFSKKNKDNIDPYIYTPFGSGPRNCIGMRFALMNMKLALIRVLQNFSFKPCKETQIPLKLSLGGLLQPEKPVVLKVESRDGTVSGA
		Gene Name		CYP3A4
		Uniprot ID		CP3A4_HUMAN
		KEGG Pathway		hsa:1576
		Protein Family		Cytochrome P450 family
		Protein Function		A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:20702771, PubMed:19965576, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:2732228, PubMed:14559847, PubMed:12865317, PubMed:15373842, PubMed:15764715, PubMed:21576599, PubMed:21490593). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:14559847, PubMed:12865317). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:2732228, PubMed:15373842, PubMed:15764715, PubMed:22773874). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:2732228, PubMed:15373842, PubMed:15764715). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981). Click to Show/Hide
Mechanism Description		Decreased metabolism of Rifabutin caused by Ritonavir mediated inhibition of CYP450 enzyme

Recommended Action
Management		To minimize the risk of rifabutin toxicity, the manufacturers suggest that rifabutin dosage be reduced to 150 mg every other day or three times per week in patients treated with ritonavir. More recently, U.S. HIV treatment guidelines and some infectious disease experts have been recommending a rifabutin dosage of 150 mg once daily or 300 mg three times per week when prescribed with ritonavir-boosted protease inhibitor regimens, as lower dosages of rifabutin have been associated with potentially subtherapeutic plasma levels in some studies. Therapeutic drug monitoring for rifabutin is advisable. Patients should be monitored closely for adverse effects of rifabutin, and a complete blood count should be performed at least weekly and as clinically indicated to monitor for development of neutropenia. Further dosage adjustments should be guided by therapeutic response and patient tolerance.

References
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8	Product Information. Mycobutin (rifabutin). Pharmacia and Upjohn, Kalamazoo, MI.
9	Product Information. Norvir (ritonavir). Abbott Pharmaceutical, Abbott Park, IL.
10	Ramachandran G, Bhavani PK, Hemanth Kumar AK, et al. "Pharmacokinetics of rifabutin during atazanavir/ritonavir co-administration in HIV-infected TB patients in India." Int J Tuberc Lung Dis 17 (2013): 1564-8. [PMID: 24200269]
11	Tanuma J, Sano K, Teruya K, et al. "Pharmacokinetics of rifabutin in Japanese HIV-infected patients with or without antiretroviral therapy." PLoS One 8 (2013): e70611. [PMID: 23940604]
12	US Food and Drug Administration "FACT SHEET FOR HEALTHCARE PROVIDERS EMERGENCY USE AUTHORIZATION FOR PAXLOVID.".
13	Zhang J, Zhu L, Stonier M, et al. "Determination of rifabutin dosing regimen when administered in combination with ritonavir-boosted atazanavir." J Antimicrob Chemother 66 (2011): 2075-82. [PMID: 21712242]
14	Jenny-Avital ER, Joseph K "Rifamycin-resistant Mycobacterium tuberculosis in the highly active antiretroviral therapy era: a report of 3 relapses with acquired rifampin resistance following alternate-day rifabutin and boosted protease inhibitor therapy." Clin Infect Dis 48 (2009): 1471-4. [PMID: 19368504]
15	Notice to readers: updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibiotrs. MMWR Morb Mortal Wkly Rep 49 (2000): 185-9. [PMID: 11795500]