ACUTE DOSE-DEPENDENT DISPOSITION STUDIES OF NICOTINIC-ACID IN RATS

The pharmacokinetics of nicotinic acid (NiAc) and nicotinuric acid (Ni UAc), the major metabolite of NiAc, and the dose dependency of these p harmacokinetics 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 administe red, and plasma and urine samples were assayed for NiAc and NiUAc by H PLC. The plasma concentration-time profiles of NiAc showed a typical c haracteristic of capacity-limited elimination after higher doses. When the NiAc dose was elevated, the total plasma clearance of NiAc decrea sed dramatically, and the normalized area under the plasma concentrati on-curve increased markedly. There was no change in the volume of dist ribution 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 unchange d 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 rem ained constant. An in vitro study of the plasma protein binding of NiA c 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-com partment model including the ''pooled'' Michaelis-Menten elimination p rocess. The present results suggest that the nonlinear disposition of NiAc can be attributed in part to the saturation of glycine conjugatio n, and also, probably to amidation.