divided by the IC50 or K i value for transporter inhibition is ≥0.1, there is potential for an in vivo drug interaction. This section highlights drug interaction studies that have been conducted in humans and evaluated for pharmacokinetic alterations of MATE substrates in the presence of inhibitors (Table 3.4).
3.6.2.1 Metformin
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
|