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% ± 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; T(max) = 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.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.