Pentazocine (PTZ), a narcotic-antagonist analgesic, is widely used in the management of patients with postoperative pain or initial carcinogenic pain.1) PTZ is a cationic drug having physicochemical properties of high lipophilicity, 2) and immediately reaches the brain in rats when the drug is administered parenterally. 3,4) In rats, brain-plasma concentration ratio is relatively constant, and PTZ concentration in the brain is much higher than that in the corresponding plasma. 5,6) The blood-brain barrier (BBB) appears to have little restricting effect on the uptake of this drug by the brain after parenteral administration in rats.We recently demonstrated that the major factor governing the uptake of PTZ into the brain was not only nonsaturable process but also carrier-mediated transport with a low-affinity saturable process, using the in situ rat brain perfusion technique.7) The advantage of this in situ technique is the high sensitive ability to estimate the kinetic parameters representing the individual rate process. 8,9) Moreover, this technique has greater advantages to the use of perfusate because the composition and flow rate can be adjusted according to the needs of the individual experiments. 8,9) However, this technique is too complex technically, because at least 3 arteries and veins must be ligated before perfusion. 8,9) On the other hand, the carotid injection technique can maintain the cerebral endothelial cells and vasculature of a brain in their normal physiological states and anatomical positions in the animal. Furthermore, the carotid injection technique is technically simpler than the brain perfusion technique. 8,9) Therefore, we investigated the influx transport mechanism of PTZ at the BBB in rats using the carotid injection technique, and compared the results with those from the in situ perfusion technique. The composition of Sosegon ® injection was PTZ (30 mg), lactic acid (12 ml) and sodium chloride (2.8 mg) in 1 ml of distilled water for injection. The PTZ powder used as a free base was from Kobayashi Kako Co., Ltd. (Fukui, Japan), which was used to adjust the drug concentration of the injection solution after dissolving in 0.1 M hydrochloric acid. Xylazine hydrochloride (Sigma Chemical Co., St. Louis, MO, U.S.A.) and ketamine hydrochloride (Ketaral ® 50; Sankyo Co., Ltd., Tokyo, Japan) were used as anesthetics. Amantadine hydrochloride, choline chloride, cimetidine, desipramine hydrochloride, ketotifen fumarate salt, hemicholinium-3, imipramine hydrochloride, lidocaine hydrochloride, mepyramine maleate, naloxone hydrochloride, propranolol hydrochloride and tetraethylammonium chloride (TEA) were purchased from Sigma Chemical Co. (St. Louis, MO, U.S.A.). Diphenhydramine hydrochloride, phenylalanine and HEPES were obtained from Wako Pure Chemical Industries, Ltd. (Osaka, Japan). Procainamide hydrochloride was purchased from Aldrich Chemical Co., Inc. (Milwaukee, WI, U.S.A.). Buprenorphine hydrochloride (Lepetan injection) was purchased from Otsuka Pharmaceutical Co., Ltd. (Tokyo, Japan), bu...

The involvement of P-glycoprotein (P-gp) in buprenorphine (BNP) transport at the blood-brain barrier (BBB) in rats was investigated in vivo by means of both the brain uptake index technique and the brain efflux index technique. P-gp inhibitors, such as cyclosporin A, quinidine and verapamil, enhanced the apparent brain uptake of [3H]BNP by 1.5-fold. The increment of the BNP uptake by the brain suggests the involvement of a P-gp efflux mechanism of BNP transport at the BBB. [3H]BNP was eliminated with an apparent elimination half-life of 27.5 min after microinjection into the parietal cortex area 2 regions of the rat brain. The apparent efflux clearance of [3H]BNP across the BBB was 0.154 ml/min/g brain, which was calculated from the elimination rate constant (2.52 x 10- 2 min- 1) and the distribution volume in the brain (6.11 ml/g brain). The efflux transport of [3H]BNP was inhibited by range from 32 to 64% in the presence of P-gp inhibitors. The present results suggest that BNP is transported from the brain across the BBB via a P-gp-mediated efflux transport system, at least in part.

The efflux transport of pentazocine (PTZ) from the brain across the blood-brain barrier (BBB) was investigated using the Brain Efflux Index method. PTZ was eliminated with the apparent elimination half-life of 13.0 min after microinjection into the parietal cortex area 2 region of the rat brain. The apparent efflux clearance of PTZ across the BBB was 137 microl/min/g brain, which was calculated from the elimination rate constant (5.35 x 10(-2) min(-1) and the distribution volume in the brain (2.56 ml/g brain). The efflux transport of PTZ was decreased in the presence of unlabeled PTZ, suggesting that PTZ is eliminated by a carrier-mediated transport system across the BBB. To characterize the efflux transport of PTZ from the brain in vivo, the effects of several compounds on the efflux transport of PTZ were investigated. P-glycoprotein (P-gp) inhibitors (verapamil and quinidine) reduced the PTZ efflux transport. In addition, the efflux transport of PTZ was inhibited by organic cations such as l-carnitine and tetraethylammonium (TEA), whereas organic anions such as p-aminohippuric acid, probenecid and taurocholate did not affect the PTZ efflux transport. The present results suggest that PTZ is transported from the brain across the BBB via l-carnitine/TEA-sensitive carrier-mediated efflux transport system(s) in addition to P-gp.

The involvement of P-glycoprotein (P-gp) in pentazocine (PTZ) transport at the blood-brain barrier (BBB) in rats was evaluated by means of an in vivo study using the brain uptake index (BUI) method. The amount of radioactivity in the brain was estimated at different intervals (up to 240 s) after carotid injection in rats. The apparent elimination rate constant (k test ) due to efflux of PTZ from the brain was calculated as 0.22 min -1 mM) of PTZ in the injection solution. The apparent uptake of PTZ by the brain increased in the presence of P-gp inhibitors such as cyclosporin A, quinidine, verapamil and vinblastine after the carotid injection. These results suggest that the increment of PTZ uptake by the brain could be explained by the saturable efflux transport system involving a P-gp-mediated efflux mechanism of PTZ transport at the BBB.