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Turnover Modeling of Non-Esterified Fatty Acids in Rats after Multiple Intravenous Infusions of Nicotinic Acid

The objective of this investigation was to use a pharmacokinetic (PK)/pharmacodynamic (PD) approach to describe and evaluate a PK model of nicotinic acid (NiAc) in guinea pigs and a PD feedback model of changes in non-esterified fatty acid (NEFA) concentrations in rats following multiple intravenous infusions of NiAc at different rates and durations of inhouse and literature (NEFA after extravascular NiAc dosing) data. Serial arterial blood samples were taken for evaluation of NiAc exposure in guinea pigs and NEFA in rats. The biophase kinetics of NiAc was assumed to impact on NEFA turnover with feedback incorporated via an inhibitory moderator compartment. The response acted linearly on the production of moderator, which then acted inversely on the turnover rate of response. The potency, expressed as the amount of NiAc in the biophase causing a 50 % inhibitory effect (ID50 ), was 6.5 nmol ± 31 % and the half-life of response (t1/2, kout ) 2 min ± 18 %. The half-life of tolerance (t1/2, ktol ) was 9 min ± 27 %. The model can be used to provide information about factors that determine the time course of NEFA response following different rates and routes of administration of NiAc or NiAc analogues.