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

Suzuki, Toyofumi; Oshimi, Masakazu; Tomono, Kazuo; Hanano, Manabu; Watanabe, Jun

doi:10.1002/jps.10224

Cited by 22 publications

(32 citation statements)

References 34 publications

(36 reference statements)

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“…When the uptake of PTZ was measured by the in situ brain perfusion technique, the apparent influx transport of PTZ was saturable, with a K m value of 2.9 mM. 7) In the present study, the apparent value of K t (3.7 mM) was in good agreement with that reported previously. A high similarity between these techniques was shown in the influx transport system of PTZ with low-affinity at the BBB.…”

Section: Discussionsupporting

confidence: 92%

“…2), indicating that PTZ is taken up into the brain in a pH-dependent manner as in a previous study. 7) This observation is in agreement with the effect of pH for cationic drugs such as lidocaine, mepyramine or propranolol using in vivo carotid injection technique. 14,15) The concentration-dependent uptake of PTZ at pH 5.5 showed the participation of a saturable uptake process (Fig.…”

Section: Discussionsupporting

confidence: 84%

“…Our previous brain perfusion study showed no inhibitory effect by choline on the influx transport of PTZ. 7) In the present study, however, choline or hemicholimium-3 inhibited slightly the PTZ uptake. Although the choline transport system [20][21][22] may be involved in the influx transport of PTZ at the BBB, this apparently different result for choline between in vivo and in situ techniques may be due to the differences between the experimental techniques.…”

Section: Discussioncontrasting

confidence: 71%

“…7) To clarify the characterization of PTZ transport at the BBB under physiological conditions, which maintain intact cerebral endothelial cells and vasculature of the brain, the present study was performed using the in vivo carotid injection technique.…”

Section: Discussionmentioning

confidence: 99%

“…However, the process has another possibility that the other low affinity carrier-mediated transport system remains as suggested in our previous perfusion study. 7) PTZ transport at the BBB was inhibited by several cationic drugs such as lidocaine, 14) propranolol, 14) mepyramine, [15][16][17] diphenhydramine 18) and amantadine, 19) which are transported into the brain via the specific carrier system for cationic drugs ( Table 1). The inhibitory effect on the influx transport was especially shown in lidocaine, propranolol or diphenhydramine by both the in vivo carotid injection and in situ brain perfusion techniques.…”

Section: Discussionmentioning

confidence: 99%

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

Suzuki

Moriki

Goto

et al. 2002

Biological & Pharmaceutical Bulletin

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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...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 84%

Section: Discussioncontrasting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Suzuki

Moriki

Goto

et al. 2002

Biological & Pharmaceutical Bulletin

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Permeability: Blood–Brain Barrier

2012

Absorption and Drug Development

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Possible involvement of cationic‐drug sensitive transport systems in the blood‐to‐brain influx and brain‐to‐blood efflux of amantadine across the blood–brain barrier

Suzuki

Fukami

Tomono

2014

Biopharm & Drug Disp

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The purpose of this study was to characterize the brain-to-blood efflux transport of amantadine across the blood-brain barrier (BBB). The apparent in vivo efflux rate constant for [(3) H]amantadine from the rat brain (keff ) was found to be 1.53 × 10(-2) min(-1) after intracerebral microinjection using the brain efflux index method. The efflux of [(3) H]amantadine was inhibited by 1-methyl-4-phenylpyridinium (MPP(+) ), a cationic neurotoxin, suggesting that amantadine transport from the brain to the blood across the BBB potentially involves the rat plasma membrane monoamine transporter (rPMAT). On the other hand, other selected substrates for organic cation transporters (OCTs) and organic anion transporters (OATs), as well as inhibitors of P-glycoprotein (P-gp), did not affect the efflux transport of [(3) H]amantadine. In addition, in vitro studies using an immortalized rat brain endothelial cell line (GPNT) showed that the uptake and retention of [(3) H]amantadine by the cells was not changed by the addition of cyclosporin, which is an inhibitor of P-gp. However, cyclosporin affected the uptake and retention of rhodamine123. Finally, the initial brain uptake of [(3) H]amantadine was determined using an in situ mouse brain perfusion technique. Notably, the brain uptake clearance for [(3) H]amantadine was significantly decreased with the co-perfusion of quinidine or verapamil, which are cationic P-gp inhibitors, while MPP(+) did not have a significant effect. It is thus concluded that while P-gp is not involved, it is possible that rPMAT and the cationic drug-sensitive transport system participate in the brain-to-blood efflux and the blood-to-brain influx of amantadine across the BBB, respectively.

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

Cited by 22 publications

References 34 publications

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

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

Permeability: Blood–Brain Barrier

Possible involvement of cationic‐drug sensitive transport systems in the blood‐to‐brain influx and brain‐to‐blood efflux of amantadine across the blood–brain barrier

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