Table 3.

Overview of in vitro Drug-Metabolizing Enzyme and Transporter-Mediated DDI Studies by Approved GLP-1 RAs and a Dual GLP-1/GIP RA

	Enzyme		Transporter
Drug	Mediator	Mechanism	Mediator	Mechanism
		Results		Results
		Potential Clinical Outcome		Potential Clinical Outcome
Exenatide	–
Liraglutide39	CYP 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4	Inhibition	–
		IC50 > 100 μM
		Low
Dulaglutide	–
Semaglutide56,57,139	CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5	Inhibition	P-gp, and BCRP	Inhibition
		*		*
		Low		Low
	CYP1A2, 2B6, and 3A4/5	Induction	OATP1B1, OATP1B3, OAT1, OAT3, and OCT2	Inhibition
		*		OATP1B1 IC50: 3.50 μM OATP1B3 IC50: 2.95 μM (Without BSA)
		Low		Low
Tirzepatide58	CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5	Inhibition	P-gp, and BCRP	Inhibition
		IC50 > 100 μM		IC50 > 100 μM
		Low		Low
	CYP1A2, 2B6, 2C8, 2C9, C19, 2D6, and 3A4/5	Induction	OCT1, OCT2, OAT1, OAT3 OATP1B1 and OATP1B3	Inhibition
		*		OATP1B1 IC50: 15.65 μM OATP1B3 IC50: 2.81 μM (Without BSA)
		Low		Low
			MATE1 and MATE2-K	Inhibition
				*
				Low

Notes: –, not determined; *, weak or no inhibition/induction.

Abbreviations: DDI, drug-drug interaction; CYP, cytochrome P450; IC₅₀, half maximal inhibitory concentration; P-gp, P-glycoprotein; BCRP, breast cancer resistance protein; OATP, organic anion transporting polypeptide; OAT, organic anion transporter; OCT, organic cation transporter; BSA, bovine serum albumin; UGT, uridine diphosphate-glucuronosyltransferase; MATE, multidrug and toxin extrusion protein.