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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). The observed BUI values of [(3)H]-PTZ (0.35 microM) were not significantly different between 5 and 15 s after the carotid injection. The concentration-dependent uptake of PTZ by the brain was increased gradually by increasing the concentration (0.01-1 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.

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., (Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2346-2353, 2002)

The influx transport mechanism of pentazocine (PTZ) at the blood-brain barrier (BBB) was investigated in rats using the carotid injection technique. The uptake kinetics of PTZ into the rat brain exhibited saturability, which occurred by both nonsaturable and carrier-mediated transport processes. The in vivo kinetic parameters were estimated as follows: the maximal uptake rate (Jmax), 3.6 +/- 1.2 micromol/min/g brain and the apparent Michaelis constant (K1), 3.7 +/- 1.7 mM for the saturable component of PTZ into the brain, and the nonsaturable uptake rate constant (Kd), 0.06 +/- 0.04 ml/min/g brain. The uptake of PTZ by the brain was strongly inhibited by lidocaine, imipramine and propranolol, and also by H1-antagonists such as mepyramine, diphenhydramine. In addition, narcotic-antagonist analgesic (buprenorphine, butorphanol or eptazocine) and an opioid antagonist (naloxone) significantly inhibited PTZ transport. These results suggest that PTZ permeates into the brain via a carrier-mediated transport system, which may widely recognize the cationic drugs.

Nifedipine-containing calcium phosphate cement (CPC) was prepared, and nifedipine (NF) release from this preparation was evaluated by the shaking method (SK), Japanese Pharmacopoeia XIV (JPXIV) paddle method (PD), and JPXIV flow-through cell method (FT). The release of NF from the CPC preparation continued for 7 d or longer by all these methods. This suggests that the release of NF can be controlled by preparing NF-containing CPC. The release pattern of NF from CPC in these tests was found to follow the Higuchi equation. However, the Higuchi constant differed among the three dissolution tests, probably because the apparent tortuosity of capillary system (tau) varied.