title: 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 (PS(inf)) 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 (V(max)), 27.2 +/- 5.2 nmol/s/g brain; apparent Michaelis constant (K(m)) for the saturable component of PTZ uptake, 2.9 +/- 0.5 mM; nonsaturable uptake rate constant (K(d)), 1.5 +/- 0.3 microL/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.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan. tsuzuki@pha.nihon-u.ac.jp
authors.forename: Toyofumi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Masakazu
authors.initials: M
authors.lastname: Oshimi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tomono
authors.forename: Manabu
authors.initials: M
authors.lastname: Hanano
authors.forename: Jun
authors.initials: J
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D005260:Female; D010423:Pentazocine / Q000493:pharmacokinetics*; D010477:Perfusion / Q000379:methods; D051381:Rats; D017208:Rats, Wistar
chemical_list: D010423:Pentazocine