BackgroundCardiac 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 pigs was evaluated using compartmental and recirculatory models.MethodsTwenty‐four premedicated pigs were evaluated during halothane (0.6‐2%) anesthesia. They were assigned randomly to one of three groups. One group served as control. In the other groups, the baseline CO was decreased or 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 and mixed‐effects approach) and a recirculatory model, which can describe lung uptake and early distribution.ResultsThe CO of individual pigs varied from 1.33 to 6.44 l/min. Three‐compartmental modeling showed that CO is a determinant of the central compartment volume (V1, r2= 0.54), fast peripheral compartment volume (V2, r2= 0.29), steady state distribution volume (Vss, r2= 0.29), fast distribution clearance (Cl12, r2= 0.39), and elimination clearance (Cl10, r2= 0.51). Recirculatory modeling showed that CO is a determinant of total distribution volume (r2= 0.48), elimination clearance (r2= 0.54), and some distribution clearances. The pulmonary distribution volume was independent of CO.ConclusionsCardiac output markedly influences the pharmacokinetics of alfentanil in pigs. Therefore, accounting for CO enhances the predictive value of pharmacokinetic models of alfentanil.