Details of Drug Interaction | MecDDI

Drug General Information (ID: DDI1WK9GSF)
Drug Name			Rosiglitazone		Drug Info		Lapatinib		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Thiazolidinediones				Antineoplastics
Structure

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

Drug Name		Rosiglitazone				Lapatinib
Mechanism		CYP450 2C8 substrate				CYP450 2C8 inhibitor
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 2C8				× Structure Sequence MEPFVVLVLCLSFMLLFSLWRQSCRRRKLPPGPTPLPIIGNMLQIDVKDICKSFTNFSKVYGPVFTVYFGMNPIVVFHGYEAVKEALIDNGEEFSGRGNSPISQRITKGLGIISSNGKRWKEIRRFSLTTLRNFGMGKRSIEDRVQEEAHCLVEELRKTKASPCDPTFILGCAPCNVICSVVFQKRFDYKDQNFLTLMKRFNENFRILNSPWIQVCNNFPLLIDCFPGTHNKVLKNVALTRSYIREKVKEHQASLDVNNPRDFIDCFLIKMEQEKDNQKSEFNIENLVGTVADLFVAGTETTSTTLRYGLLLLLKHPEVTAKVQEEIDHVIGRHRSPCMQDRSHMPYTDAVVHEIQRYSDLVPTGVPHAVTTDTKFRNYLIPKGTTIMALLTSVLHDDKEFPNPNIFDPGHFLDKNGNFKKSDYFMPFSAGKRICAGEGLARMELFLFLTTILQNFNLKSVDDLKNLNTTAVTKGIVSLPPSYQICFIPV
		Gene Name		CYP2C8
		Uniprot ID		CP2C8_HUMAN
		KEGG Pathway		hsa:1558
		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:7574697, PubMed:11093772, PubMed:14559847, PubMed:15766564, 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:7574697, PubMed:11093772, PubMed:14559847, PubMed:15766564, PubMed:19965576). Primarily catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) with a preference for the last double bond (PubMed:7574697, PubMed:15766564, PubMed:19965576). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes all trans-retinoic acid toward its 4-hydroxylated form (PubMed:11093772). Displays 16-alpha hydroxylase activity toward estrogen steroid hormones, 17beta-estradiol (E2) and estrone (E1) (PubMed:14559847). Plays a role in the oxidative metabolism of xenobiotics. It is the principal enzyme responsible for the metabolism of the anti-cancer drug paclitaxel (taxol) (PubMed:26427316). Click to Show/Hide
Mechanism Description		Decreased metabolism of Rosiglitazone caused by Lapatinib mediated inhibition of CYP450 enzyme

Recommended Action
Management		Given the potential for dose-related adverse events with rosiglitazone, caution is advised during coadministration with CYP450 2C8 inhibitors, particularly in patients already receiving a higher dosage of rosiglitazone (e.g., 8 mg/day). Close monitoring for the development of hypoglycemia and other adverse effects is recommended, such as fluid retention weight gain new or worsening heart failure pulmonary, peripheral, and macular edema angina bone fractures anemia and liver enzyme elevations. Patients should regularly monitor their blood sugar and learn how to recognize and treat hypoglycemia, which may include symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, and palpitation. The dosage of rosiglitazone may require adjustment if an interaction is suspected. Likewise, patients should be observed for potential loss of glycemic control following discontinuation of the CYP450 2C8 inhibitor, and the rosiglitazone dosage adjusted as necessary.

References
1	Baldwin SJ, Clarke SE, Chenery RJ "Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone." Br J Clin Pharmacol 48 (1999): 424-32. [PMID: 10510156]
2	Hruska MW, Amico JA, Langaee TY, Ferrell RE, Fitzgerald SM, Frye RF "The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects." Br J Clin Pharmacol 59 (2005): 70-9. [PMID: 15606443]
3	Niemi M, Backman JT, Granfors M, Laitila J, Neuvonen M, Neuvonen PJ "Gemfibrozil considerably increases the plasma concentrations of rosiglitazone." Diabetologia 46 (2003): 1319-23. [PMID: 12898007]
4	Niemi M, Backman JT, Neuvonen PJ "Effects of trimethoprim and rifampin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone." Clin Pharmacol Ther 76 (2004): 239-49. [PMID: 15371985]
5	Product Information. Avandia (rosiglitazone) SmithKline Beecham, Philadelphia, PA.
6	Scheen AJ "Pharmacokinetic interactions with thiazolidinediones." Clin Pharmacokinet 46 (2007): 1-12. [PMID: 17201456]
7	Wen X, Wang JS, Backman JT, Laitila J, Neuvonen PJ "Trimethoprim and sulfamethoxazole are selective inhibitors of CYP2C8 and CYP2C9, respectively." Drug Metab Dispos 30 (2002): 631-635. [PMID: 12019187]