Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI9EGS8NH)
Drug Name			Rifabutin		Drug Info		Saquinavir		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antibiotics				Anti-Hiv Agents
Structure

Mechanism of Rifabutin-Saquinavir Interaction (Severity Level: Moderate)
CYP450 enzyme induction Click to Show/Hide Mechanism Graph

Drug Name		Rifabutin				Saquinavir
Mechanism		CYP450 3A4 inducer				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		Increased metabolism of Saquinavir caused by Rifabutin mediated induction of CYP450 enzyme

Recommended Action
Management		No dose adjustment of saquinavir/ritonavir (1000 mg/100 mg twice a day) is recommended if used in combination with rifabutin. However, it is recommended that the dose of rifabutin be reduced to 150 mg every other day or three times per week. Patients receiving the combination should also be monitored for liver enzyme elevations and other potential signs and symptoms of rifabutin toxicity such as leukopenia, uveitis, arthralgia, and skin discoloration. Plasma concentration monitoring of rifabutin may be considered. Rifabutin should not be used with saquinavir mesylate in the absence of ritonavir as a pharmacokinetic booster. In addition, unboosted saquinavir is not indicated as the sole protease inhibitor in the treatment of HIV-infected adults it should only be given with low-dose ritonavir in combination with other antiretroviral agents. In general, treatment of tuberculosis (TB) and Mycobacterium avium-intracellulare complex in the context of antiretroviral therapy is complex and requires an individualized approach. Experts in the treatment of these conditions should be consulted.

References
1	American Thoracic Society, CDC, Infectious Diseases Society of America "Treatment of tuberculosis." MMWR Morb Mortal Wkly Rep 52(RR-11) (2003): 1-77. [PMID: 12836625]
2	Burman WJ, Jones BE "Treatment of HIV-related tuberculosis in the era of effective antiretroviral therapy." Am J Respir Crit Care Med 164 (2001): 7-12. [PMID: 11435232]
3	Cerner Multum, Inc. "Australian Product Information.".
4	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
5	Moyle GJ, Buss NE, Goggin T, Snell P, Higgs C, Hawkins DA "Interaction between saquinavir soft-gel and rifabutin in patients infected with HIV." Br J Clin Pharmacol 54 (2002): 178-82. [PMID: 12207638]
6	Product Information. Invirase (saquinavir). Roche Laboratories, Nutley, NJ.
7	Durant J, Clevenbergh P, Garraffo R, Halfon P, Icard S, DelGiudice P, Montagne N, Schapiro JM, Dellamonica P "Importance of protease inhibitor plasma levels in HIV-infected patients treated with genotypic-guided therapy: pharmacological data from the Viradapt Study." Aids 14 (2000): 1333-9. [PMID: 10930147]
8	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]