Details of Drug Interaction | MecDDI

Drug General Information (ID: DDIL3UTXVD)
Drug Name			Olanzapine		Drug Info		Obeticholic acid		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Antipsychotic Agents				Gi Agents
Structure

Mechanism of Olanzapine-Obeticholic acid Interaction (Severity Level: Moderate)
CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph

Drug Name		Olanzapine				Obeticholic acid
Mechanism		CYP450 1A2 substrate				CYP450 1A2 inhibitor
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 1A2				× Structure Sequence MALSQSVPFSATELLLASAIFCLVFWVLKGLRPRVPKGLKSPPEPWGWPLLGHVLTLGKNPHLALSRMSQRYGDVLQIRIGSTPVLVLSRLDTIRQALVRQGDDFKGRPDLYTSTLITDGQSLTFSTDSGPVWAARRRLAQNALNTFSIASDPASSSSCYLEEHVSKEAKALISRLQELMAGPGHFDPYNQVVVSVANVIGAMCFGQHFPESSDEMLSLVKNTHEFVETASSGNPLDFFPILRYLPNPALQRFKAFNQRFLWFLQKTVQEHYQDFDKNSVRDITGALFKHSKKGPRASGNLIPQEKIVNLVNDIFGAGFDTVTTAISWSLMYLVTKPEIQRKIQKELDTVIGRERRPRLSDRPQLPYLEAFILETFRHSSFLPFTIPHSTTRDTTLNGFYIPKKCCVFVNQWQVNHDPELWEDPSEFRPERFLTADGTAINKPLSEKMMLFGMGKRRCIGEVLAKWEIFLFLAILLQQLEFSVPPGVKVDLTPIYGLTMKHARCEHVQARLRFSIN
		Gene Name		CYP1A2
		Uniprot ID		CP1A2_HUMAN
		KEGG Pathway		hsa:1544
		Protein Family		Cytochrome P450 family
		Protein Function		A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids, steroid hormones and vitamins (PubMed:9435160, PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576). 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) (PubMed:9435160, PubMed:10681376, PubMed:11555828, PubMed:12865317, PubMed:19965576). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:11555828, PubMed:12865317). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2 (PubMed:11555828, PubMed:12865317). Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). May act as a major enzyme for all-trans retinoic acid biosynthesis in the liver. Catalyzes two successive oxidative transformation of all-trans retinol to all-trans retinal and then to the active form all-trans retinoic acid (PubMed:10681376). Primarily catalyzes stereoselective epoxidation of the last double bond of polyunsaturated fatty acids (PUFA), displaying a strong preference for the (R,S) stereoisomer (PubMed:19965576). Catalyzes bisallylic hydroxylation and omega-1 hydroxylation of PUFA (PubMed:9435160). May also participate in eicosanoids metabolism by converting hydroperoxide species into oxo metabolites (lipoxygenase-like reaction, NADPH-independent) (PubMed:21068195). Plays a role in the oxidative metabolism of xenobiotics. Catalyzes the N-hydroxylation of heterocyclic amines and the O-deethylation of phenacetin (PubMed:14725854). Metabolizes caffeine via N3-demethylation (Probable). Click to Show/Hide
Mechanism Description		Decreased metabolism of Olanzapine caused by Obeticholic acid mediated inhibition of CYP450 enzyme

Recommended Action
Management		Caution is advised when obeticholic acid is prescribed with drugs that undergo metabolism by CYP450 1A2, particularly those with a narrow therapeutic range such as theophylline or tizanidine. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever obeticholic acid is added to or withdrawn from therapy.

References
1	Albers LJ, Ozdemir V, Marder SR, et al. "Low-dose fluvoxamine as an adjunct to reduce olanzapine therapeutic dose requirements: a prospective dose-adjusted drug interaction strategy." J Clin Psychopharmacol 25 (2005): 170-174. [PMID: 15738749]
2	Bergemann N, Frick A, Parzer P, Kopitz J "Olanzapine plasma concentration, average daily dose, and interaction with co-medication in schizophrenic patients." Pharmacopsychiatry 37 (2004): 63-8. [PMID: 15048613]
3	Brosen K, Skjelbo E, Rasmussen BB, Poulsen HE, Loft S "Fluvoxamine is a potent inhibitor of cytochrome P4501A2." Biochem Pharmacol 45 (1993): 1211-4. [PMID: 8466541]
4	Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM "Olanzapine. Pharmacokinetic and pharmacodynamic profile." Clin Pharmacokinet 37 (1999): 177-93. [PMID: 10511917]
5	Cerner Multum, Inc. "UK Summary of Product Characteristics.".
6	Chiu CC, Lane HY, Huang MC, et al. "Dose-dependent alternations in the pharmacokinetics of olanzapine during coadministration of fluvoxamine in patients with schizophrenia." J Clin Pharmacol 44 (2004): 1385-90. [PMID: 15545309]
7	de Jong J, Hoogenboom B, van Troostwijk LD, de Haan L "Interaction of olanzapine with fluvoxamine." Psychopharmacology (Berl) 155 (2001): 219-20. [PMID: 11401013]
8	Desai HD, Seabolt J, Jann MW "Smoking in patients receiving psychotropic medications: a pharmacokinetic perspective." CNS Drugs 15 (2001): 469-94. [PMID: 11524025]
9	Gex-Fabry M, Balant-Gorgia AE, Balant LP "Therapeutic drug monitoring of olanzapine: the combined effect of age, gender, smoking, and comedication." Ther Drug Monit 25 (2003): 46-53. [PMID: 12548144]
10	Gossen D, de Suray JM, Vandenhende F, Onkelinx C, Gangji D "Influence of fluoxetine on olanzapine pharmacokinetics." AAPS PharmSci 4 (2002): E11. [PMID: 12102620]
11	Hiemke C, Peled A, Jabarin M, et al. "Fluvoxamine augmentation of olanzapine in chronic schizophrenia: pharmacokinetic interactions and clinical effects." J Clin Psychopharmacol 22 (2002): 502-6. [PMID: 12352274]
12	Letsas KP, Sideris A, Kounas SP, Efremidis M, Korantzopoulos P, Kardaras F "Drug-induced QT interval prolongation after ciprofloxacin administration in a patient receiving olanzapine." Int J Cardiol 109 (2006): 273-4. [PMID: 15935493]
13	Markowitz JS, DeVane CL "Suspected ciprofloxacin inhibition of olanzapine resulting in increased plasma concentration." J Clin Psychopharmacol 19 (1999): 289-91. [PMID: 10350045]
14	Product Information. Lybalvi (olanzapine-samidorphan). Alkermes, Inc, Cambridge, MA.
15	Product Information. Qelbree (viloxazine). Supernus Pharmaceuticals Inc, Rockville, MD.
16	Product Information. Zyprexa (olanzapine). Lilly, Eli and Company, Indianapolis, IN.
17	Wang CY, Zhang ZJ, Li WB, et al. "The differential effects of steady-state fluvoxamine on the pharmacokinetics of olanzapine and clozapine in healthy volunteers." J Clin Pharmacol 44 (2004): 785-92. [PMID: 15199083]
18	Weigmann H, Gerek S, Zeisig A, Muller M, Hartter S, Hiemke C "Fluvoxamine but not sertraline inhibits the metabolism of olanzapine: evidence from a therapeutic drug monitoring service." Ther Drug Monit 23 (2001): 410-3. [PMID: 11477325]