Effects of proton pump inhibitors on metformin pharmacokinetics and pharmacodynamics.
As inhibitors of organic cation transporters (OCTs), proton pump inhibitors (PPIs) may affect the plasma levels of metformin, an OCT substrate. We investigated the effects of two PPIs, pantoprazole and rabeprazole, on metformin pharmacokinetics and glucose levels in healthy subjects. In this open, randomized, six-sequence, three-period crossover study, 24 participants were administered metformin, either alone or in combination with pantoprazole or rabeprazole. The plasma concentrations of metformin and serum concentrations of glucose after a 75-g oral glucose tolerance test (OGTT) were determined. The area under the concentration-time curve (AUC) for metformin was 15% and 16% greater following coadministration with pantoprazole and rabeprazole, respectively. The maximum plasma metformin concentrations (Cmax) also increased by 15% and 22%, respectively, compared with when it was administered without the PPIs. The percentage change in the AUC for glucose concentration versus time for metformin plus rabeprazole was significantly lower than that for metformin plus pantoprazole [geometric mean ratio: 0.96 (90% confidence interval: 0.92-0.99) and 0.77 (0.63-0.93), respectively]. There was no significant difference in the maximum glucose concentration. In conclusion, concomitant administration of PPIs with metformin significantly increased plasma metformin exposure, but the effects on glucose disposition were minor and varied depending on the PPI administered.
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.).
AnHye
A
Kim
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.).
Inbum
I
Chung
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.).
Seo Hyun
SH
Yoon
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.).
Kyung-Sang
KS
Yu
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.).
Kyoung Soo
KS
Lim
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.).
Joo-Youn
JY
Cho
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.).
Howard
H
Lee
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.).
In-Jin
IJ
Jang
Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Korea (A.H.K., I.C., S.H.Y., K.-S.Y., K.S.L., J.-Y.C., H.L., I.-J.J.); Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Korea (J.Y.C.) jychung@snubh.org.
Jae Yong
JY
Chung
D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D018592:Cross-Over Studies; D004347:Drug Interactions; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D008687:Metformin / Q000493:pharmacokinetics / Q000494:pharmacology*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D054328:Proton Pump Inhibitors; D008687:Metformin