Acute dose-dependent disposition studies of nicotinic acid in rats

The pharmacokinetics of nicotinic acid (NiAc) and nicotinuric acid (NiUAc), the major metabolite of NiAc, and the dose dependency of these pharmacokinetics were determined in rats. Intravenous injections of 2, 5, 15, and 45 mg/kg of NiAc and 5 and 15 mg/kg of NiUAc were administered, and plasma and urine samples were assayed for NiAc and NiUAc by HPLC. The plasma concentration-time profiles of NiAc showed a typical characteristic of capacity-limited elimination after higher doses. When the NiAc dose was elevated, the total plasma clearance of NiAc decreased dramatically, and the normalized area under the plasma concentration-curve increased markedly. There was no change in the volume of distribution at steady state. After the administration of NiUAc, however, the pharmacokinetics of NiUAc were linear, at least up to a dose of 15 mg/kg. With increasing doses of NiAc, the ratio for NiUAc to unchanged drug excreted in urine decreased markedly from 4.54 +/- 0.93 at 2 mg/kg to 0.37 +/- 0.12 at 45 mg/kg while the renal clearance of NiAc remained constant. An in vitro study of the plasma protein binding of NiAc showed no saturability, with a 40 to 50% bound fraction, when total NiAc concentrations were 1 to 130 mu g/ml. Plasma NiAc profiles after the iv administration of NiAc were adequately described by the two-compartment model including the ''pooled'' Michaelis-Menten elimination process. The present results suggest that the nonlinear disposition of NiAc can be attributed in part to the saturation of glycine conjugation, and also, probably to amidation.