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A human drug interaction study was conducted to determine the effect of peficitinib 150 mg (single dose on days 3 and 5–11) (janus kinase inhibitor; rheumatoid arthritis indication) and its metabolite on the pharmacokinetics of metformin (750 mg on Days 1 and 10) [91]. Initial peficitinib in vitro assessments reported an IC₅₀ of 10 μmol/l for MATE1. Expected unbound Cmax concentrations for peficitinib were 0.44 μmol/l. This would result in a Cmax/IC₅₀ quotient of 0.044, suggesting low potential for a clinical interaction. Clinical results showed reduced AUC, Cmax, and renal clearance of metformin with the addition of peficitinib. However, these changes in metformin pharmacokinetics were not considered clinically actionable.

Two studies were conducted to determine whether histamine H2 antagonists impact metformin pharmacokinetics. A study in healthy volunteers (n = 12) evaluated the influence of famotidine (200 mg day 1 and 800 mg day 2), a MATE1 inhibitor, on the pharmacokinetics and pharmacodynamics of metformin [92]. In vitro studies calculated an IC₅₀ of 0.25 μM for famotidine on MATE1, and with an unbound Cmax of 1 μM, a clinical interaction was predicted (Cmax/IC₅₀: 0.25). In the presence of famotidine, a significant increase in metformin exposure and bioavailability and a decrease in renal secretory clearance were demonstrated. The concurrent administration of famotidine also significantly reduced the glucose exposure curve as well as creatinine urinary excretion. The same group of investigators evaluated the effect of nizatidine, a histamine H2 and MATE2‐K inhibitor, on the pharmacokinetics and pharmacodynamics of metformin in healthy volunteers (n = 12) [93]. In vitro nizatidine has an IC₅₀ of 7.81 μmol/l on MATE2. The unbound Cmax for nizatidine is 2.88 μmol/l suggesting the potential for a drug–drug interaction (Cmax/IC₅₀: 0.37). In the presence of nizatidine, a significant increase in metformin volume of distribution and reduction in the glucose exposure curve, without an impact on renal secretory clearance, was reported.

Abemaciclib is a cyclin‐dependent kinase inhibitor prescribed for the treatment of advanced breast cancer. Measurement of IC₅₀ values for MATE1 (0.52 μM) and MATE2‐K (0.75 μM) inhibition by abemaciclib (unbound Cmax of 0.03 μM) suggested a low likelihood of a clinical drug interaction, with Cmax/IC₅₀ quotients of 0.05 and 0.04 for MATE1 and MATE2‐K, respectively. In a clinical study (n = 40), abemaciclib increased the metformin area under the concentration–time curve by 37%. Metformin Cmax was also increased in combination with abemaciclib, and the renal clearance and secretion clearance were decreased. Assessment of kidney function failed to demonstrate any significant changes consistent with renal toxicity due to abemaciclib. A clinically significant interaction between abemaciclib and metformin was supported by the study data.

The effects of pyrimethamine, a known MATE inhibitor, on plasma concentrations and renal clearance of metformin and blood glucose outcomes were evaluated in healthy male volunteers (n = 20) [94]. Subjects received two doses of metformin, with or without pyrimethamine. Total Cmax of pyrimethamine was expected to be 8.3 μM (unbound Cmax 7.22 μM) and in vitro IC₅₀ values of 0.11 and 0.1 μM, for MATE1 and MATE2, respectively. Cmax/IC₅₀ quotients were calculated as 65 and 72 predicting in vivo interactions. When pyrimethamine was co‐administered, the metformin exposure was 2.58‐fold greater and renal clearance was 0.28‐fold lower. Despite increased exposures and reduced renal clearance, the effects on blood glucose were actually reduced and not increased, leading the authors to speculate that uptake transporters and gastrointestinal mechanisms of action may also be important in determining the overall impact on metformin therapy in the presence of MATE inhibitors.

TABLE 3.3 MATE1 and MATE2‐K substrates used in humans

Indication	Drug	Cl total (ml/min)a	Cl renal (ml/min)a	Fe	Dose (mg)b	F	Estimated AUC (Dose*F/Cl)
Allergy	Fexofenadine	27.3–36.3 l/h	3–4 l/h	0.11	60	NR	1.88 mg h/l
Anesthesia	Vecuronium	3–4.5 ml/min/kg	0.45–0.67 ml/min/kg	0.15	0.1 mg/kg	1.0	133 μg min/ml
Anticoagulation	Dabigatran	2,410	1,928	0.80	150	0.03–0.07	3.1 μg min/ml
Anti‐infective	Cephalexin	280	252	0.90	250	1.0	893 μg min/ml
Cephradine	420	378	0.9	500	0.9	1.07 mg min/ml
Levofloxacin	144–226	96–142	0.87	750	0.99	3.9 mg min/ml
Norfloxacin	916	275	0.30	400	0.35	153 μg min/ml
Anti‐malarial	Chloroquine	0.35 l/h/kg	0.1 l/kg/h	0.65–0.70	500	0.99	1,414 mg h/l/kg
Antiviral	Acyclovir	759	759	Extensive	400	0.15	79 μg min/ml
Ganciclovir	62 ml/min/kg	3.1 ml/min/kg	0.05	1,000	0.05	806 μg min/ml/kg
Lamivudine	399	280	0.70	100	0.86	216 μg min/ml
Tenofovir disoproxil fumarate	503–606 ml/h/kg	161–194 ml/h/kg	0.32	300	0.25	136 μg h/ml/kg
Entecavir	588.1	360–471	0.62–0.73	1	1.0	1.7 μg min/ml
Asthma	Ipratropium	2,325	65.1	0.028	0.25	0.07	7.5 ng min/ml
Zafirlukast	19.4 l/h	1.9 l/h	0.10	20	NR	1.0 mg h/l
Cancer	Cisplatin	250–350 ml/min/m2	50–62 ml/min/m2	0.13–0.17	50 mg/m2	1.0	166 μg min/ml
Topotecan	36–132 l/h/m2	10.0–37.0 l/h/m2	0.03–0.51	1.5 mg/m2	1.0	17.9 μg h/l
Oxaliplatin	18.5–31.5 l/h	10–17 l/h	0.54	85 mg/m2	1.0	3.5 mg h/l
Imatinib	8–14 l/h	0.72–1.26 l/h	0.05–0.13	400	0.98	36 mg h/l
Mesna/dimesna	1.23 l/h/kg	0.41 l/h/kg	0.33	5,000	0.89	3,618 mg h/l/kg
Cardiovascular	Procainamide	705	391	0.3–0.6	500	1.0	709 μg min/ml
Amiodarone	87.5	0	<1%	400	0.5	2.3 mg min/ml
Quinidine	2.8	0.7	0.05–0.20	200	0.7	50 mg min/ml
Depression	Imipramine	1 l/h/kg	0.001 l/h/kg	0.001	100 mg	0.95	95 mg h/l/kg
Diabetes	Metformin	542–642	542–642	1	850	0.55	779 μg min/ml
Hypertension	Captopril	0.8 l/h/kg	0.4 l/kg/h	0.95	25	0.75	23.4 mg h/l/kg
Diltiazem	11.8 ml/min/kg	4.13 ml/min/kg	0.35	120	0.95	9.7 mg min/ml/kg
Verapamil	10.4–12.4 ml/h/kg	7.3–8.7 ml/h/kg	0.70	120	0.20–0.35	2.9 mg h/l/kg
Clonidine	180–390	133	0.40–0.60	0.1	0.90	0.3 μg min/ml
Atenolol	100–176	95–168	0.40–0.50	50	0.50	17.8 μg min/ml
Nadolol	2.78–3.22 ml/min/kg	0.9–1.92 ml/min/kg	0.25	40	0.30	4.0 mg min/ml/kg
Leg cramps	Quinine	0.17 l/h/kg	0.034 l/h/kg	0.20	650	0.76–0.88	3,058 mg h/l/kg
Reflux disease	Cimetidine	30–48 l/h	13.8–30 l/h	0.48	400	0.73	7.3 mg h/l

^a Units reported other than ml/min are delineated.

^b Units reported other than mg are delineated.

TABLE 3.4 MATE1 and MATE2‐K inhibitors identified in human studies

Indication	Druga	Dose
Asthma	Zafirlukast	20 mg
Cancer	Imatinib	400 mg
Cardiovascular	Ranolazine	1,000 mg
Emesis	Ondansetron	8 mg
Infections	Pyrimethamine	50 mg
Trimethoprim	200 mg
Dolutegravir	50 mg
Isavuconazole	200 mg
Levofloxacin	750 mg
Ciprofloxacin	500 mg
Cetirizine	10 mg
Cephalexin	500 mg
Cephradine	500 mg
Cobicistat	150 mg
Indinavir	800 mg
Ritonavir	100 mg
Reflux disease	Cimetidine	400 mg
Ranitidine	300 mg
Famotidine	200 mg
Nizatidine	600 mg

^a Studies identifying these chemicals vary in design and include single and multidose regimens.

The ability of pyrimethamine to cause a drug interaction with metformin was assessed in healthy volunteers (n = 8) using a micro‐dose (100 μg) or low therapeutic dose (250 mg) of metformin [95]. The K _i values of pyrimethamine for hMATE1, hMATE2‐K, and hOCT2 were reported to be 93, 59, and 10 μmol/l, respectively. The K _i values for MATE1 and MATE2‐K were lower in this study than previous reports [96]. Pyrimethamine administration reduced the renal clearance of metformin 23% with the micro‐dose and 35% with a low therapeutic dose of metformin. At the low therapeutic dosing, Cmax and exposure to metformin were elevated. At both the micro‐dose and therapeutic dose, pyrimethamine significantly reduced creatinine clearance, fraction excreted, and renal clearance of metformin, demonstrating the utility of using micro‐dosing of metformin to predict drug–drug interactions. However, the magnitude of changes was more pronounced at the therapeutic dosing scheme.

Given the well‐established interactions between triazole antifungals and drug transporters (and metabolism enzymes), a phase 1 clinical trial for isavuconazole examined the potential for drug–drug interactions with several transporters using probe substrates [97]. It was also anticipated that the new antifungal would be co‐administered with several immunosuppressants in the clinical environment, which might predispose patients to potential drug–drug interactions. The potential interactions with OCT1/2 and MATE1 were conducted using metformin as the substrate after 6 days of oral isavuconazole in healthy controls (n = 21). Previous in vitro assessments of isavuconazole in MATE1‐HEK293 cells demonstrated an IC₅₀ of 6.31 μmol/l with ¹⁴C‐metformin as a substrate. Expected Cmax for isavuconazole was reported as <7 μg/ml, and it is >99% protein bound (0.07 μg/ml or 0.16 μmol/l unbound Cmax). The calculated Cmax/IC₅₀ quotient would be 0.024, which is less than the threshold for predicting a clinical interaction. Nonetheless, metformin exposures and Cmax were ~50% and 23% higher in the presence versus absence of isavuconazole, respectively, suggesting a drug–drug interaction.