Pharmacokinetics of metformin after enteral administration in insulin-resistant ponies

Abstract

Objective - To determine pharmacokinetics and plasma steady-state kinetics of metformin after oral or nasogastric administration in insulin-resistant (IR) ponies. Animals - 8 IR ponies. Procedures - Metformin (30 mg/kg) was administered to 8 ponies via nasogastric tube. Blood samples were collected at intervals for 24 hours. Plasma concentrations of metformin were measured via liquid chromatography-electrospray tandem mass spectroscopy. Pharmacokinetic variables were determined via noncompartmental analysis. Metformin (15 mg/kg, PO, twice daily [8 am and 5 pm]) was administered to 4 ponies for an additional 20 days, and blood samples were obtained every 2 days. Plasma concentration at steady state (Css) was determined. Results - Mean ± SD elimination half-life (t1/2) of metformin was 11.7 ± 5.2 hours, maximal plasma concentration was 748 ± 269 ng/mL at 54 ± 32 minutes, mean area under the curve was 355 ± 92 μg•h/mL, and apparent clearance was 90.6 ± 28.1 mL/min/kg. The Css was 122 ± 22 ng/mL. Conclusions and Clinical Relevance - Metformin reportedly enhances insulin sensitivity of peripheral tissues without stimulating insulin secretion, but bioavailability in horses is low. The t1/2 of metformin in IR ponies was similar to that in humans. Actual clearance of metformin adjusted for bioavailability in IR ponies was similar to that in humans; however, during chronic oral administration at dosages reported in efficacy studies, the Css of metformin was less than values associated with therapeutic efficacy in humans. The apparent lack of long-term efficacy of metformin in horses is likely attributable to low bioavailability, rather than to rapid clearance.