Investigation on the Influx Transport Mechanism of Pentazocine at the Blood-Brain Barrier in Rats Using the Carotid Injection Technique.

Abstract

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...

Brainpeps: the blood–brain barrier peptide database

“…From the data obtained with the BUI method (see ''The in vivo permeability''), another kinetic parameter, the brain uptake rate (J [nt -1 m -1 ]), could be calculated as (Pardridge 1995;Suzuki et al 2002):…”

Small molecular drug transfer across the blood-brain barrier via carrier-mediated transport systems

“…The in vivo uptake of pentazocine, a narcotic-antagonist analgesic, by rat brain was significantly inhibited by lidocaine, imipramine and propranolol, as well as by H1 antagonists such as mepyramine and diphenhydramine. 71 Pentazocine, in spite of efflux transport by P-glycoprotein at the BBB, is also highly distributed into brain by a carriermediated transport system that may widely recognize cationic drugs.…”

Involvement of P-glycoprotein in Blood-Brain Barrier Transport of Pentazocine in Rats Using Brain Uptake Index Method

“…2,3) These results may be explained by the saturation of the efflux transport from the brain capillary endothelial cells.…”

“…We recently demonstrated that PTZ is transported predominantly via a carrier-mediated influx system at the blood-brain barrier (BBB) in rats, using both the brain uptake index (BUI) method 2) and an in situ brain perfusion technique.…”