RT Journal Article
SR Electronic
T1 Metformin Sinusoidal Efflux from the Liver Is Consistent with Negligible Biliary Excretion and Absence of Enterohepatic Cycling
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1967
OP 1971
DO 10.1124/dmd.113.053025
VO 41
IS 11
A1 Maciej J. Zamek-Gliszczynski
A1 Jing Q. Bao
A1 Jeffrey S. Day
A1 J. William Higgins
YR 2013
UL http://dmd.aspetjournals.org/content/41/11/1967.abstract
AB 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% ± 0.1% of the metformin oral dose was present in the liver (liver/plasma ratio = 4.5 ± 0.6) over a pharmacologically relevant dose and time range in mice (10–300 mg/kg; 1.5–2.5 hours; Tmax = 1.4 ± 0.5; bioavailability > 59%). Distribution to the kidneys was not markedly higher, which contained 0.87% ± 0.08% of the oral dose (kidney/plasma ratio = 11.9 ± 1.1). However, only 0.11% ± 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% ± 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% ± 39.3% versus 0.222% ± 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.