TISSUE DISTRIBUTION OF FENTANYL AND ALFENTANIL IN THE RAT CANNOT BE DESCRIBED BY A BLOOD-FLOW LIMITED MODEL

Traditionally, physiological pharmacokinetic models assume that arteri al blood flow to tissue is the rate-limiting step in the transfer of d rug into tissue parenchyma. When this assumption is made the tissue ca n be described as a well-stirred single compartment. This study presen ts the tissue washout concentration curves of the two opioid analgesic s fentanyl and alfentanil after simultaneous 1-min iv infusions in the rat and explores the feasibility of characterizing their tissue pharm acokinetics, modeling each of the 12 tissues separately, by means of e ither a one-compartment model or a unit disposition function. The tiss ue and blood concentrations of the two opioids were measured by gas-li quid chromatography. The well-stirred one-compartment tissue model cou ld reasonably predict the concentration-time course of fentanyl in the heart, pancreas, testes, muscle, and fat, and of alfentanil in the br ain and heart only. In most other tissues, the initial uptake of the o pioids was considerably lower than predicted by this model. The unit d isposition functions of the opioids in each tissue could be estimated by nonparametric numerical deconvolution, using the arterial concentra tion times tissue bloodflow as the input and measured tissue concentra tions as the response function. The observed zero-time intercepts of t he unit disposition functions were below the theoretical value of one, and were invariably lower for alfentanil than for fentanyl These find ings can be explained by the existence of diffusion barriers within th e tissues and they also indicate that alfentanil is less efficiently e xtracted by the tissue parenchyma than the more lipophilic compound fe ntanyl. The individual unit disposition functions obtained for fentany l and alfentanil in 12 rat tissues provide a starting point for the de velopment of models of intratissue kinetics of these opioids. These su bmodels can then be assembled into full physiological models of drug d isposition.