Effect of lactic acidosis on lidocaine pharmacokinetics in pigs
Date of Completion
Health Sciences, Pharmacology|Biology, Animal Physiology|Health Sciences, Pharmacy
The pharmacokinetics of lidocaine has been shown to be greatly changed in certain clinical conditions and thus, may affect its pharmacological effect. A preliminary study on lidocaine in acute acidosis in pigs showed a statistically significant decrease in its clearance. The underlying mechanism for this kinetic change is unknown and may be due to (1) alteration of lidocaine ionization state affecting its plasma protein binding and tissue distribution; (2) impairment of liver metabolism and decrease in hepatic blood flow affecting lidocaine hepatic elimination. ^ The aim of the present study are: (1) to characterize the effect of acute acidosis on the disposition kinetics of lidocaine; (2) to identify the factors associated with the acidosis-induced alteration of lidocaine kinetics; and (3) to predict lidocaine concentration-time profile in the blood and tissues under acidosis condition. ^ A lidocaine pharmacokinetic study was carried out in 12 farm pigs (randomized to either lactic acidosis or control group). Lidocaine concentrations in the blood, plasma, and tissues, plasma protein binding, tissue-to-blood partition coefficient, regional blood flow, hepatic extraction ratio and organ tissue weight were measured using appropriate, validated methods. ^ The results showed that plasma lidocaine concentration-time profiles were best fitted by a two-compartment pharmacokinetic model. The lidocaine elimination half-life and steady-state volume of distribution were significantly increased, and the total body clearance decreased in the acidosis group compared to the control. Also, a significant decrease in lidocaine plasma protein binding during acidosis was observed. The tissue-to-blood partition coefficients for majority of tissues, except kidney, were significantly lower during acidosis compared to the control. Lidocaine hepatic extraction ratio determined at the end of the experiment was also significantly lower during acidosis. These observed changes were incorporated in a physiologically-based pharmacokinetic model and the model was able to predict the observed lidocaine concentrations in the blood and tissues. ^ The results of the present study provide a better understanding of the effect of acute systemic acidosis on the kinetics of lidocaine. Such information should help optimize lidocaine therapy. Furthermore, the concept of systemic acidosis-induced changes in drug kinetics may be applicable to many other weak basic drugs as well. ^
Zhao, Hong, "Effect of lactic acidosis on lidocaine pharmacokinetics in pigs" (1999). Doctoral Dissertations. AAI9942604.