Details of Drug Interaction | MecDDI

Drug General Information (ID: DDISKDZ5H1)
Drug Name			Tadalafil		Drug Info		Tipranavir		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Impotence Agents				Anti-Hiv Agents
Structure

Mechanism of Tadalafil-Tipranavir Interaction (Severity Level: Moderate)
CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph

Drug Name		Tadalafil				Tipranavir
Mechanism		CYP450 3A4 substrate				CYP450 3A4 inhibitor
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 Tadalafil caused by Tipranavir mediated inhibition of CYP450 enzyme

Recommended Action
Management		Caution is advised if tadalafil is administered in combination with protease inhibitors. For the treatment of erectile dysfunction, the dosage of tadalafil should not exceed 10 mg once every 72 hours when used on an as-needed basis in patients receiving PI therapy. When given for once-daily use in the treatment of erectile dysfunction or benign prostatic hyperplasia, the maximum recommended dose is 2.5 mg. For the treatment of pulmonary arterial hypertension, tadalafil should be started at 20 mg once daily in patients who have been receiving ritonavir-boosted PI therapy for at least one week. The dosage may be increased to 40 mg once daily based upon individual tolerability. The use of tadalafil for PAH should be avoided during the initiation of ritonavir-boosted PI therapy. The manufacturers recommend that tadalafil be discontinued at least 24 hours prior to initiating the PIs. After at least one week, tadalafil may be resumed at 20 mg once daily, and the dosage increased to 40 mg once daily based upon individual tolerability. There is no need to discontinue tadalafil when initiating PI therapy that does not contain ritonavir as a pharmacokinetic booster, nor wait at least one week after PI therapy to start tadalafil. The tadalafil dosage should be initiated at or adjusted to 20 mg once daily when coadministered with nonritonavir-boosted PI regimens, then increased to 40 mg as tolerated. All patients treated with tadalafil should be advised to promptly notify their physician if they experience pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

References
1	Loulergue P, Gaillard R, Mir O "Interaction involving tadalafil and CYP3A4 inhibition by ritonavir." Scand J Infect Dis 43 (2011): 239-40. [PMID: 20942777]
2	Product Information. Adcirca (tadalafil). United Therapeutics Corporation, Silver Spring, MD.
3	Product Information. Aptivus (tipranavir). Boehringer-Ingelheim, Ridgefield, CT.
4	Product Information. Cialis (tadalafil). Lilly, Eli and Company, Indianapolis, IN.
5	Product Information. Crixivan (indinavir). Merck & Co, Inc, West Point, PA.
6	Product Information. Invirase (saquinavir). Roche Laboratories, Nutley, NJ.
7	Product Information. Kaletra (lopinavir-ritonavir) Abbott Pharmaceutical, Abbott Park, IL.
8	Product Information. Lexiva (fosamprenavir). GlaxoSmithKline, Research Triangle Park, NC.
9	Product Information. Prezista (darunavir). Ortho Biotech Inc, Bridgewater, NJ.
10	Product Information. Reyataz (atazanavir). Bristol-Myers Squibb, Princeton, NJ.
11	Product Information. Viracept (nelfinavir). Agouron Pharma Inc, La Jolla, CA.