The effect of the fat content of food on the pharmacokinetics and pharmacodynamics of SDZ FOX 988, an antidiabetic agent, in the dog.
SDZ FOX 988 (FOX 988) is being developed for the treatment of type II diabetes. The objective of this study was to examine the effect of the fat content of food on the pharmacokinetics and pharmacodynamics of FOX 988 following oral administration in the dog. In a randomized, cross-over design, four dogs received a single 10 mg kg-1 dose of 14C-FOX 988 suspension concomitantly with food containing 10% fat or 40% fat, or with the 10% fat food at 4 h post-dose. Serial blood, urine, and fecal samples were collected for 96 h and analyzed for total radioactivity. Blood concentrations of 53-450, the active metabolite of FOX 988, were also determined. Serum concentrations of beta-hydroxybutyrate and glucose, pharmacological markers for the antidiabetic effects, were measured serially for 24 h after dosing. The animals receiving the low-fat meal at dosing and at 4 h post-dose exhibited similar extents of absorption, as shown by similar AUC values and urinary radioactivity recovery. Administration of the high-fat meal at dosing significantly enhanced the absorption of FOX 988 and resulted in high blood concentrations of 53-450. However, no significant differences in the pharmacological activity of the drug were observed among the three treatments.
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Drug Metabolism and Pharmacokinetics Department, Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
Kalafsky
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Aun
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Tse
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D020155:3-Hydroxybutyric Acid; D000042:Absorption; D000098:Acetophenones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000284:Administration, Oral; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage* / Q000032:analysis; D004285:Dogs; D005504:Food Analysis; D006801:Humans; D006885:Hydroxybutyrates / Q000097:blood; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male
D000098:Acetophenones; D001565:Benzoates; D001786:Blood Glucose; D004041:Dietary Fats; D006885:Hydroxybutyrates; D007004:Hypoglycemic Agents; C094090:SDZ 53-450; C094089:SDZ FOX 988; D020155:3-Hydroxybutyric Acid