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Article

Meta-Assessment of Metformin Absorption and Disposition Pharmacokinetics in Nine Species

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY 14214, USA
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Author to whom correspondence should be addressed.
Academic Editors: Jung-woo Chae and In-hwan Baek
Pharmaceuticals 2021, 14(6), 545; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060545
Received: 5 May 2021 / Revised: 24 May 2021 / Accepted: 28 May 2021 / Published: 7 June 2021
The objective of this study was to systematically assess literature datasets and quantitatively analyze metformin PK in plasma and some tissues of nine species. The pharmacokinetic (PK) parameters and profiles of metformin in nine species were collected from the literature. Based on a simple allometric scaling, the systemic clearances (CL) of metformin in these species highly correlate with body weight (BW) (R2 = 0.85) and are comparable to renal plasma flow in most species except for rabbit and cat. Reported volumes of distribution (VSS) varied appreciably (0.32 to 10.1 L/kg) among species. Using the physiological and anatomical variables for each species, a minimal physiologically based pharmacokinetic (mPBPK) model consisting of blood and two tissue compartments (Tissues 1 and 2) was used for modeling metformin PK in the nine species. Permeability-limited distribution (low fd1 and fd2) and a single tissue-to-plasma partition coefficient (Kp) value for Tissues 1 and 2 were applied in the joint mPBPK fitting. Nonlinear regression analysis for common tissue distribution parameters along with species-specific CL values reasonably captured the plasma PK profiles of metformin across most species, except for rat and horse with later time deviations. In separate fittings of the mPBPK model to each species, Tissue 2 was considered as slowly-equilibrating compartment consisting of muscle and skin based on in silico calculations of the mean transit times through tissues. The well-fitted mPBPK model parameters for absorption and disposition PK of metformin for each species were compared with in vitro/in vivo results found in the literature with regard to the physiological details and physicochemical properties of metformin. Bioavailability and absorption rates decreased with the increased BW among the species. Tissues such as muscle dominate metformin distribution with low permeability and partitioning while actual tissue concentrations found in rats and mice show likely transporter-mediated uptake in liver, kidney, and gastrointestinal tissues. Metformin has diverse pharmacologic actions, and this assessment revealed allometric relationships in its absorption and renal clearance but considerable variability in actual and modeled tissue distribution probably caused by transporter differences. View Full-Text
Keywords: metformin; pharmacokinetics; absorption; disposition; allometric scaling; minimal physiologically based pharmacokinetic modeling metformin; pharmacokinetics; absorption; disposition; allometric scaling; minimal physiologically based pharmacokinetic modeling
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MDPI and ACS Style

Jeong, Y.-S.; Jusko, W.J. Meta-Assessment of Metformin Absorption and Disposition Pharmacokinetics in Nine Species. Pharmaceuticals 2021, 14, 545. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060545

AMA Style

Jeong Y-S, Jusko WJ. Meta-Assessment of Metformin Absorption and Disposition Pharmacokinetics in Nine Species. Pharmaceuticals. 2021; 14(6):545. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060545

Chicago/Turabian Style

Jeong, Yoo-Seong, and William J. Jusko. 2021. "Meta-Assessment of Metformin Absorption and Disposition Pharmacokinetics in Nine Species" Pharmaceuticals 14, no. 6: 545. https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060545

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