Metformin Sinusoidal Efflux from the Liver Is Consistent with Negligible Biliary Excretion and Absence of Enterohepatic Cycling

Abstract

Although metformin hepatic distribution is critical to pharmacological activity, the drug is cleared by urinary excretion. Metformin hepatobiliary disposition was studied in rodents representative of clinical pharmacokinetics to elucidate why metformin is not appreciably eliminated in bile. On average, 1.0% 6 0.1% of the metformin oral dose was present in the liver (liver/plasma ratio = 4.5 6 0.6) over a pharmacologically relevant dose and time range in mice (10-300 mg/kg; 1.5-2.5 hours; T max = 1.4 6 0.5; bioavailability > 59%). Distribution to the kidneys was not markedly higher, which contained 0.87% 6 0.08% of the oral dose (kidney/plasma ratio = 11.9 6 1.1). However, only 0.11% 6 0.02% of the intravenous and bioavailable oral dose was recovered in bile, suggesting that biliary excretion is not the only route of clearance for hepatic metformin. Consistent with negligible biliary excretion, pharmacokinetics were unaffected by bile duct cannulation, proving the effective absence of enterohepatic cycling. In single-pass liver perfusion studies, 2.4% 6 0.3% of the perfused metformin dose was distributed to the liver, which underwent >300-fold greater sinusoidal than biliary excretion during the subsequent drug-free washout perfusion (74.0% 6 39.3% versus 0.222% 6 0.003% recovery of hepatic metformin in perfusate versus bile, respectively). These studies demonstrate that despite similar magnitude of metformin liver and kidney distribution, metformin biliary excretion is negligible due to predominant sinusoidal efflux from the liver.

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

“…This difference is consistent with the presence of other distributional compartments for metformin in vivo, including the small intestine, kidney, liver, and skeletal muscle (Wilcock and Bailey, 1994;Scheen, 1996). Distribution into these organs is a carrier-facilitated process, and thus distributional equilibrium is achieved faster in vivo (Gong et al, 2012;Zamek-Gliszczynski et al, 2013a). Although metformin tissue distribution does not stand out as particularly high individually [e.g., kidney/plasma ratio: 11.9 6 1.1; and liver/ plasma ratio: 4.5 6 0.6 in mice (Zamek-Gliszczynski et al, 2013a)], collectively these additional sites of distribution contribute to the higher partitioning rate observed in vivo.…”

“…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).…”

“…Distribution into these organs is a carrier-facilitated process, and thus distributional equilibrium is achieved faster in vivo (Gong et al, 2012;Zamek-Gliszczynski et al, 2013a). Although metformin tissue distribution does not stand out as particularly high individually [e.g., kidney/plasma ratio: 11.9 6 1.1; and liver/ plasma ratio: 4.5 6 0.6 in mice (Zamek-Gliszczynski et al, 2013a)], collectively these additional sites of distribution contribute to the higher partitioning rate observed in vivo. This explanation of the in vitro versus in vivo discrepancy in rate constants is supported by the PBPK model ( Figs.…”

Short term uptake and transport process for metformin in roots of Phragmites australis and Typha latifolia

“…OCT-mediated transport is generally considered electrogenic and independent from sodium. The primary driving force is supplied simply by the electrochemical gradient of the transported compounds or the electronegative membrane potential (Klaassen and Aleksunes, 2010;Zamek-Gliszczynski et al, 2013). However, in recently published studies OCT-mediated transport was also described to occur via cation exchange (Budiman et al, 2000;Pelis et al, 2012).…”

Pharmacokinetic and toxicological considerations for the treatment of diabetes in patients with liver disease

“…Recent experimental data in animals showed that metformin sinusoidal efflux from the liver is consistent with negligible biliary excretion and absence of enterohepatic cycling [24].…”