Dose-Independent Pharmacokinetics of Metformin in Rats: Hepatic and Gastrointestinal First-Pass Effects

Choi, Young Hee; Kim, Sang G.; Lee, Myung G.

doi:10.1002/jps.20744

Cited by 108 publications

(129 citation statements)

References 21 publications

(39 reference statements)

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“…Recent work with single-pass intestinal perfusion in rats with metformin showed that permeability in the duodenum was concentrationdependent, suggesting the involvement of a carrier-mediated saturable mechanism (Song et al, 2006). Conversely, other researchers concluded that there was a dose-independent linear absorption of metformin in rats (Choi et al, 2006), although the doses used in this study were high (50 -200 mg/kg), thus potentially saturating any carriermediated absorption over the dose range examined. It is clear that the mechanisms responsible for the dose-dependent absorption of metformin in humans need to be better understood.…”

mentioning

confidence: 57%

Mechanisms Underlying Saturable Intestinal Absorption of Metformin

Proctor¹,

Bourdet²,

Thakker³

2008

Drug Metab Dispos

113

104

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ABSTRACT:The purpose of the study was to elucidate mechanisms of metformin absorptive transport to explain the dose-dependent absorption observed in humans. Apical (AP) and basolateral (BL) uptake and efflux as well as AP to BL (absorptive) transport across Caco-2 cell monolayers were evaluated over a range of concentrations. Transport was concentration-dependent and consisted of saturable and nonsaturable components (K m ϳ 0.05 mM, J max ϳ 1.0 pmol min ؊1 cm ؊2, and K d, transport ϳ 10 nl min ؊1 cm ؊2 ). AP uptake data also revealed the presence of saturable and nonsaturable components (K m ϳ 0.9 mM, V max ϳ 330 pmol min ؊1 mg of protein ؊1, and K d, uptake ϳ 0.04 l min ؊1 mg of protein ؊1 ). BL efflux was rate-limiting to transcellular transport of metformin; AP efflux was 7-fold greater than BL efflux and was not inhibited by N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GW918), a P-glycoprotein inhibitor. AP efflux was trans-stimulated by metformin and prototypical substrates of organic cation transporters, suggesting that a cation-specific bidirectional transport mechanism mediated the AP efflux of metformin. BL efflux of intracellular metformin was much less efficient in comparison with the overall transport, with BL efflux clearance accounting for ϳ7 and ϳ13% of the overall transport clearance at 0.05 and 10 mM metformin concentrations, respectively. Kinetic modeling of cellular accumulation and transport processes supports the finding that transport occurs almost exclusively via the paracellular route (ϳ90%) and that the paracellular transport is saturable. This report provides strong evidence for a saturable mechanism in the paracellular space and provides insight into possible mechanisms for the dose dependence of metformin absorption in vivo.

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mentioning

confidence: 57%

Mechanisms Underlying Saturable Intestinal Absorption of Metformin

Proctor¹,

Bourdet²,

Thakker³

2008

Drug Metab Dispos

113

104

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“…However, few in vivo experimental strategies are available to distinguish the absorption and first-pass metabolism in the gut. Most studies determined the total gastrointestinal bioavailability (F X ·F G ) (Raoof et al, 1996;Hashimoto et al, 1998;Mihara et al, 2001;Choi et al, 2006;Hanada et al, 2008;Bae et al, 2009;Gertz et al, 2011) or minimized the interference of the other by using a model drug of which metabolism is negligible (Kagan et al, 2010) or specific inhibitors (Shirasaka et al, 2011). Although predictions can be made by in vitro methods, a simple extrapolation from in vitro to in vivo has considerable limitations because various factors may affect the absorption and metabolism in the gastrointestinal tract.…”

Section: Discussionmentioning

confidence: 99%

“…Especially, distinguishing between the contributions of gut wall absorption and first-pass metabolism, which compose the gastrointestinal bioavailability, will provide useful information for the development of novel apicidin analogs with improved bioavailability. Nevertheless, experimental separation of the fraction absorbed-that is, the net transport of unchanged drug into the gastrointestinal tract (F X )-and the fraction that is not metabolized through the gut wall (F G ) in vivo is not easily achieved, and most of the literature reports them together as gastrointestinal bioavailability (F X ·F G ) (Raoof et al, 1996;Hashimoto et al, 1998;Mihara et al, 2001;Choi et al, 2006;Hanada et al, 2008;Bae et al, 2009;Gertz et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Quantitative Determination of Absorption and First-Pass Metabolism of Apicidin, a Potent Histone Deacetylase Inhibitor

et al. 2014

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Apicidin, a potential oral chemotherapeutic agent, possesses potent anti-histone-deacetylase activity. After oral administration, the total bioavailability of apicidin is known to be low (14.2%-19.3%). In the present study, we evaluated the factors contributing to the low bioavailability of apicidin by means of quantitative determination of absorption fraction and first-pass metabolism after oral administration. Apicidin was given to rats by five different routes: into the femoral vein, duodenum, superior mesenteric artery, portal vein, and carotid artery. Especially, the fraction absorbed (F X ) and the fraction that is not metabolized in the gut wall (F G ) were separated by injection of apicidin via superior mesenteric artery, which enables bypassing the permeability barrier. The F X was 45.9% 6 9.7%, the F G was 70.9% 6 8.1% and the hepatic bioavailability (F H ) was 70.6% 6 12.3%, while the pulmonary firstpass metabolism was minimal (F L = 102.8% 6 7.4%), indicating that intestinal absorption was the rate-determining step for oral absorption of apicidin. The low F X was further examined in terms of passive diffusion and transporter-mediated efflux by in vitro immobilized artificial membrane (IAM) chromatographic assay and in situ single-pass perfusion method, respectively. Although the passive diffusion potential of apicidin was high (98.01%) by the IAM assay, the in situ permeability was significantly enhanced by the presence of the P-glycoprotein (P-gp) inhibitor elacrider. These data suggest that the low bioavailability of apicidin was mainly attributed to the P-gp efflux consistent with the limited F X measured in vivo experiment.

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“…In vitro rat blood metformin (1-20 mg/ml) B/P was previously reported to be 0.7-0.8 at 2 hours (Choi et al, 2006). Although the Choi et al values are consistent with the initial B/P in the present study (Table 1), as well as with the in vivo value (B/P , 1) at 2 hours after oral dosing (Tucker et al, 1981), this 2-hour B/P value does not represent distributional equilibrium (Noel, 1979).…”

Section: Discussionmentioning

confidence: 98%

“…Metformin is eliminated rapidly and efficiently by the kidneys, the sole clearing organ for this drug (Glucophage, 2009). Metformin's renal extraction ratio is 90%-100% in mice, rats, and humans (plasma renal clearance approximates renal plasma flow rate) (Davies and Morris, 1993;Choi et al, 2006;Glucophage, 2009;Higgins et al, 2012;Zamek-Gliszczynski et al, 2013a). Relative to the 6.2-hour plasma half-life in humans, the half-life of repartitioning from the cellular component of blood to plasma is 6-fold longer (Table 2), resulting in a longer in vivo whole-blood half-life of 17.6 hours and an even longer in vivo erythrocyte half-life of 23.4 hours (Robert et al, 2003;Glucophage, 2009).…”

Section: Discussionmentioning

confidence: 99%

Metformin's Intrinsic Blood-to-Plasma Partition Ratio (B/P): Reconciling the Perceived High In Vivo B/P > 10 with the In Vitro Equilibrium Value of Unity

Xie

Bowers

et al. 2015

J Pharmacol Exp Ther

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Blood cells are considered an important distributional compartment for metformin based on the high blood-to-plasma partition ratio (B/P) in humans (.10 at C min ). However, literature reports of metformin's intrinsic in vitro B/P values are lacking. At present, the extent and rate of metformin cellular partitioning was determined in incubations of fresh human and rat blood with [14 C]metformin for up to 1 week at concentrations spanning steady-state plasma C min , C max , and a concentration associated with lactic acidosis. The results showed that metformin's intrinsic equilibrium B/P was ∼0.8-1.4 in blood, which is ,10% of the reported clinical value. Kinetics of metformin partitioning into human blood cells and repartitioning back into plasma were slow (repartitioning half-life ∼32-39 hours). These data, along with in vivo rapid and efficient renal clearance of plasma metformin (plasma renal extraction ratio ∼90%-100%), explain why the clinical terminal half-life of metformin in plasma (6 hours) is 3-to 4-fold shorter than the half-life in whole blood (18 hours) and erythrocytes (23 hours). The rate constant for metformin repartitioning from blood cells to plasma (∼0.02 h 21) is far slower than the clinical renal elimination rate constant (0.3 h 21 ). Blood distributional rate constants were incorporated into a metformin physiologically-based pharmacokinetic model, which predicted the differential elimination half-life in plasma and blood. The present study demonstrates that the extent of cellular drug partitioning in blood observed in a dynamic in vivo system may be very different from the static in vitro values when repartitioning from blood cells is far slower than clearance of drug in plasma. IntroductionThe intrinsic rate and extent of blood cell partitioning of drugs can be reliably determined in a static in vitro system due to the absence of confounding processes present in vivo, including absorption, competing distribution to other tissues, and clearance (Hinderling, 1997). Although metformin is a first-line treatment of type 2 diabetes mellitus that has been commonly used for decades (Gong et al., 2012), its in vitro partitioning properties into the cellular component of blood have not been documented in the literature. Instead, erythrocytes are presumed to be an important distributional compartment for metformin based on the markedly longer blood versus plasma half-life in humans (Glucophage, 2009). Early clinical studies described metformin's in vivo blood-toplasma partition ratio (B/P) value as high (B/P . 10 at C min ), and partitioning as slow based on the apparent timedependent B/P, which increased over the duration of the dosing interval (Sirtori et al., 1978; Pentikainen et al., 1979;Tucker et al., 1981). Following oral administration of a single 1.5-g dose in humans, metformin B/P gradually increased from ,1 between 0 and 4 hours to .10 at 24 hours, with the B/P value becoming greater than unity at 4 hours (Tucker et al., 1981). More recent clinical studies demonstrated metformin elim...

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Dose-Independent Pharmacokinetics of Metformin in Rats: Hepatic and Gastrointestinal First-Pass Effects

Cited by 108 publications

References 21 publications

Mechanisms Underlying Saturable Intestinal Absorption of Metformin

Mechanisms Underlying Saturable Intestinal Absorption of Metformin

Quantitative Determination of Absorption and First-Pass Metabolism of Apicidin, a Potent Histone Deacetylase Inhibitor

Metformin's Intrinsic Blood-to-Plasma Partition Ratio (B/P): Reconciling the Perceived High In Vivo B/P > 10 with the In Vitro Equilibrium Value of Unity

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