Tissue distribution of fentanyl and alfentanil in the rat cannot be described by a blood flow limited model

Traditionally, physiological pharmacokinetic models assume that arterial blood flow to tissue is the rate-limiting step in the transfer of drug into tissue parenchyma. When this assumption is made the tissue can be described as a well-stirred single compartment. This study presents the tissue washout concentration curves of the two opioid analgesics fentanyl and alfentanil after simultaneous 1-min iv infusions in the rat and explores the feasibility of characterizing their tissue pharmacokinetics, modeling each of the 12 tissues separately, by means of either a one-compartment model or a unit disposition function. The tissue and blood concentrations of the two opioids were measured by gas-liquid chromatography. The well-stirred one-compartment tissue model could reasonably predict the concentration-time course of fentanyl in the heart, pancreas, testes, muscle, and fat, and of alfentanil in the brain and heart only. In most other tissues, the initial uptake of the opioids was considerably lower than predicted by this model. The unit disposition functions of the opioids in each tissue could be estimated by nonparametric numerical deconvolution, using the arterial concentration times tissue blood flow as the input and measured tissue concentrations as the response function. The observed zero-time intercepts of the unit disposition functions were below the theoretical value of one, and were invariably lower for alfentanil than for fentanyl. These findings can be explained by the existence of diffusion barriers within the tissues and they also indicate that alfentanil is less efficiently extracted by the tissue parenchyma than the more lipophilic compound fentanyl. The individual unit disposition functions obtained for fentanyl and alfentanil in 12 rat tissues provide a starting point for the development of models of intratissue kinetics of these opioids. These submodels can then be assembled into full physiological models of drug disposition.Supported in part by the National Institute on Aging, RO1-AG-4594, the Anesthesia/ Pharmacology Research Foundation, and a travel grant from Janssen Pharma AB (Sweden).