Recirculatory and compartmental pharmacokinetic modeling of alfentanil in pigs - The influence of cardiac output

Background: Cardiac output (CO) is likely to influence the pharmacokinetics of anesthetic drugs and should be accounted for in pharmacokinetic models. The influence of CO on the pharmacokinetic parameters of alfentanil in pig s was evaluated using compartmental and recirculatory models. Methods: Twenty-four premedicated pigs were evaluated during halothane (0.6 -2%) anesthesia. They were assigned randomly to one of three groups. One gr oup served as control. In the other groups, the baseline CO was decreased o r increased by 40% by pharmacologic intervention (propranolol or dobutamine ). Boluses of alfentanil (2 mg) and indocyanine green (25 mg) were injected into the right atrium. Blood samples were taken for 150 min from the right atrium and aortic root. Arterial concentration-time curves of indocyanine green and alfentanil were analyzed using compartmental models (two-stage an d mixed-effects approach) and a recirculatory model, which can describe lun g uptake and early distribution. Results: The CO of individual Digs varied from 1.33 to 6.44 1/min, Three-co mpartmental modeling showed that CO is a determinant of the central compart ment volume (V-1, r(2) = 0.54), fast peripheral compartment volume (V-2, r( 2) = 0.29), steady state distribution volume (V-65, r(2) = 0.29), fast dist ribution clearance (Cl-12, r(2) = 0,39), and elimination clearance (Cl-10, r(2) = 0.51), Recirculatory modeling showed that CO is a determinant of tot al distribution volume (r(2) = 0.48), elimination clearance (r(2) = 0.54), and some distribution clearances. The pulmonary distribution volume was ind ependent of CO. Conclusions: Cardiac output markedly influences the pharmacokinetics of alf entanil in pigs, Therefore, accounting for CO enhances the predictive value of pharmacokinetic models of alfentanil.