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 |
