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Pharmacokinetics of metformin after enteral administration in insulin-resistant ponies

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  • 1 School of Animal and Veterinary Sciences, Charles Sturt University, Wagga Wagga, NSW 2650, Australia.
  • | 2 School of Animal and Veterinary Sciences, Charles Sturt University, Wagga Wagga, NSW 2650, Australia.
  • | 3 Equine Studies Group, WALTHAM Centre for Pet Nutrition, Waltham-on-the-Wolds, Leicestershire, LE14 4RT, England.
  • | 4 Faculty of Science and Technology, Queensland University of Technology, Brisbane, QLD 4001, Australia.
  • | 5 Clinical Pharmacology and Toxicology, PathWest Laboratory Medicine, Locked Bag 2009, Nedlands, WA 6009, Australia.
  • | 6 School of Animal and Veterinary Sciences, Charles Sturt University, Wagga Wagga, NSW 2650, Australia.

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, maxima plasma concentration was 748 ± 269 ng/mL at 54 ± 32 minutes, mean area under the curve was 355 ± 92μg•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. (Am J Vet Res 2010;71:1201-1206)

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, maxima plasma concentration was 748 ± 269 ng/mL at 54 ± 32 minutes, mean area under the curve was 355 ± 92μg•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. (Am J Vet Res 2010;71:1201-1206)

Contributor Notes

Support for Ms. Tinworth was provided by WALTHAM Centre for Pet Nutrition and Rural Industries Research and Development Corporation, Australia.

The authors thank Dr. Sharanne Raidal for technical assistance and advice.

Address correspondence to Dr. Noble (gnoble@csu.edu.au).