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

Abstract

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.

Keywords: absorption; allometric scaling; disposition; metformin; minimal physiologically based pharmacokinetic modeling; pharmacokinetics.

Figure 1

Allometric relationships between literature-reported metformin $CL$ (black) and renal plasma flow ($RPF$) values (red) and body weights of 9 species (Table 3, see below). Except for rabbit and cat, the systemic clearance of metformin was comparable to $RPF$. Lines were fitted to the indicated allometric relationships ($y=a·B{W}^b$, where $BW$ is the body weight).

Figure 2

The minimal physiologically based pharmacokinetic model with two tissue compartments. A single $K_p$ value ($K_{p1}=K_{p2}$) was used in the joint fitting, while the cardiac output ($Q_{CO}$) was divided into tissue blood flow to each compartment ($Q_1+Q_2=Q_{CO}$) in the separate fittings. Symbols are defined in the text and in Table 2 and Table 5 (see below).

Figure 3

Simultaneous fitting of metformin pharmacokinetics dosed intravenously in 9 species to the minimal physiologically based pharmacokinetic model in Figure 2. Fitted profiles are in separate panels for visual clarification for the indicated species. The doses and fitted parameters are listed in Table 1 and Table 2. The three curves for man are for different doses from three studies.

Figure 4

Fitting of intravenous and oral pharmacokinetics of metformin individually for 9 species to the mPBPK model. The slowly-equilibrating compartment (Tissue 2) was assumed to consist of skin and muscle (i.e., $Q_2=Q_{SK}+Q_{MU}$, $V_2=V_{SK}+V_{MU}$). Fitted parameters are listed in Table 5.

Figure 5

Fitted pharmacokinetic parameters related to oral absorption of metformin in relation to body weights, including bioavailability ($F$), absorption rate constants ($k_a$ and $F·k_a$), and intestinal effective permeability ($P_{eff}$). The fitted parameters for each species are listed in Table 5.