Investigation of Transport Mechanism of Pentazocine across the Blood‐Brain Barrier Using the In Situ Rat Brain Perfusion Technique

Abstract

To characterize pentazocine (PTZ) transport across the blood‐brain barrier (BBB), the cerebrovascular permeability‐surface area product (PSinf) of PTZ was determined by a well‐established in situ rat brain perfusion technique. The uptake kinetics of PTZ by the rat brain exhibited saturability, which indicates the simultaneous mechanisms of carrier‐mediated transport and passive diffusion. The kinetic parameters were estimated as follows: maximal influx rate (Vmax), 27.2 ± 5.2 nmol/s/g brain; apparent Michaelis constant (Km) for the saturable component of PTZ uptake, 2.9 ± 0.5 mM; nonsaturable uptake rate constant (Kd), 1.5 ± 0.3 μL/s/g brain. BBB transport of PTZ was significantly inhibited by cationic drugs such as diphenhydramine, propranolol, and eptazocine (a narcotic‐antagonist analgesic), but not by choline, suggesting that the PTZ transport system is shared by cationic drugs. Furthermore, co‐perfusion of verapamil caused a significant (two‐fold) increase in the BBB permeability to PTZ. This finding indicates that PTZ may be a substrate of the endogenous BBB efflux transport system, P‐glycoprotein. These findings demonstrate that the primary mechanism governing the uptake of PTZ by the brain is carrier‐mediated transport, not passive diffusion. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2346–2353, 2002