PENETRATION KINETICS OF 2',3'-DIDEOXYINOSINE IN DERMIS IS DESCRIBED BY THE DISTRIBUTED MODEL

The present study evaluated the kinetics of drug penetration in the de rmis. A rat was given a dermal dose of 2',3'-dideoxyinosine (ddI). At 6 hr, the skin tissue was excised, immediately frozen and sectioned, a nd the decline of drug concentration as a function of tissue depth was determined. The tissue concentration-depth profile showed a semilogar ithmic decline, as would be expected in a distributed tissue kinetic m odel which incorporates diffusion and capillary membrane transport. Th e goodness of fit of the profiles by the simple diffusion and the dist ributed models were compared using four statistical criteria, i.e., co efficient of determination, Akaike Information criterion, Schwartz cri terion and Imbimbo criterion. These analyses showed that the decline o f tissue concentration versus tissue depth in the dermis was better de scribed by the distributed model than by the diffusion model in all 7 animals. To examine the effect of blood perfusion on the tissue concen tration-depth profiles, some of the tissues were frozen after 1 and 2 hr storage at room temperature. In contrast to the adjacent tissues fr ozen immediately, the concentration-depth profiles in tissues frozen a fter a 1-2 hr delay were described equally well by distributed and dif fusion models. A comparison of the concentration-depth profiles in the tissues processed immediately or after a delay showed a 7 fold more s hallow slope and a 60% lower concentration at the epidermis-dermis int erface after storage. However, storage did not alter the total amount of drug in the entire dermis. Drug degradation during storage was furt her ruled out by the insignificant ddI degradation in 10% skin homogen ate (a half-life of similar to 70 hr). These results indicate that und er in vitro conditions, where there is no blood flow to remove the dru g, the kinetics of drug penetration in the dermis are described by sim ple diffusion in accordance with the concentration gradient. In summar y, these data indicate the importance of capillary blood flow on drug penetration profiles in the dermis, and that concentration-depth profi les in the dermis is described by the distributed model.