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

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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

Section snippets

INTRODUCTION

Pentazocine (PTZ), a relatively short‐acting narcotic‐antagonist analgesic, is used clinically for the relief of cancer‐related or postoperative pain because it is a reasonably potent analgesic with lower abuse liability than morphine.1., 2. The analgesic effects of PTZ are caused by interactions with specific opioid receptors in the brain.2 In agreement with the rapid onset of action observed clinically,3 PTZ readily penetrates the blood‐brain barrier (BBB) and immediately reaches the brain in

Radiochemicals and Chemicals

[Ring‐1, 3‐3H]‐(+)‐pentazocine ([3H]PTZ, specific activity 1417.1 GBq (38.3 Ci)/mmol), [carboxyl14C]‐inulin‐carboxyl (specific activity 0.071 GBq (1.92 mCi)/g), [methyl3H]‐diazepam ([3H]DZP, specific activity 3071 GBq (83.0 Ci)/mmol), and [3H]‐3‐O‐methyl‐D‐glucose ([3H]3OMG, specific activity 2782.4GBq (75.2 Ci)/mmol) were purchased from New England Nuclear Co. (Boston, MA). The radiochemical purity of the [3H]PTZ used for the experiment was greater than 99%. PTZ (Sosegon® injection) was

Concentration Dependence of PTZ Uptake by the Brain

The mean Fpf and Vv through the perfused left hemisphere in separate groups of animals were calculated as 39.2 ± 2.3 μL/s/g brain and 12.8 ± 1.4 μL/g brain, respectively. These values were in good agreement with the reported Fpf and Vv at a perfusion rate of 63 μL/s.16 In preliminary experiments, we examined the period over [3H]PTZ (0.02 μM) uptake to establish the best conditions for unidirectional influx measurements. The PSinf at 35 s was not significantly different from the value determined

DISCUSSION

We first attempted to determine whether the mechanism of BBB permeability to PTZ is either passive diffusion or carrier‐mediated transport using an in situ rat brain perfusion technique.14., 17. The decrease in PSinf with increasing PTZ concentration indicates the participation of a saturable uptake process (Table 1). The analysis of uptake kinetics provided one saturable component with a Km value of 2.9 mM, Vmax value of 27.2 nmol/s/g brain, and Kd value of 1.5 μL/s/g brain. The ratio of Vmax/K

CONCLUSION

The uptake kinetics of PTZ into the rat brain suggests parallel transport by a saturable, carrier‐mediated mechanism, and a nonsaturable system of passive diffusion. BBB transport of PTZ is mediated primarily by a carrier‐mediated system, rather than by simple diffusion. The inhibition of PTZ transport by some drugs suggests that it shares a common transport system with other cationic drugs; however, it differs from the choline carrier‐mediated system. Co‐perfusion of verapamil increased BBB

Acknowledgements

This work was supported in part by the Simabara Science Promotion Foundation for 2000, by a Research Grant for Assistants provided by Nihon University Research Grant for 2000, Japan, and by a Grant‐in‐Aid for Scientific Research (No. 13672328) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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