Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIT2HE70G)
Drug Name			Cyclosporine		Drug Info		Felodipine		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antiviral Agents				Antihypertensive Agents
Structure

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

Drug Name		Cyclosporine				Felodipine
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 Felodipine caused by Cyclosporine mediated inhibition of CYP450 enzyme

Recommended Action
Management		Clinical and laboratory monitoring for altered efficacy and safety (e.g., increased cyclosporine levels, excessive hypotension, or nephrotoxicity) of both drugs is recommended during concomitant therapy and when the dose of either drug is changed or discontinued. Dosage adjustments may be required. Amlodipine undergoes less first-pass metabolism and may be considered as an alternative. Patients should be advised to notify their physician if they experience nausea, vomiting, diarrhea, abdominal pain, dizziness, syncope, fatigue, or headache.

References
1	Cohen DJ, Teng SN, Appel GB "Influence of oral felodipine on serum cyclosporine concentrations." Clin Transplant 8 (1994): 541-5. [PMID: 7865916]
2	Jacobs U, Klein B, Klehr HU "Cumulative side effects of cyclosporine and ca antagonists: hypergalactinemia, mastadenoma, and gynecomastia." Transplant Proc 26 (1994): 3122. [PMID: 7998089]
3	Madsen JK, Jensen JD, Jensen LW, Pedersen EB "Pharmacokinetic interaction between cyclosporine and the dihydropyridine calcium antagonist felodipine." Eur J Clin Pharmacol 50 (1996): 203-8. [PMID: 8737760]
4	Meredith PA, Elliott HL "Clinical pharmacokinetics of amlodipine." Clin Pharmacokinet 22 (1992): 22-31. [PMID: 1532771]
5	Pedersen EB, Sorensen SS, Eiskjaer H, et al "Interaction between cyclosporine and felodipine in renal transplant recipients." Kidney Int 41 (1992): s82-6. [PMID: 1614074]
6	Sketris IS, Methot ME, Nicol D, Belitsky P, Knox MG "Effect of calcium-channel blockers on cyclosporine clearance and use in renal transplant patients." Ann Pharmacother 28 (1994): 1227-31. [PMID: 7849332]