The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jun 2005
Mediation of highly concentrative uptake of pregabalin by L-type amino acid transport in Chinese hamster ovary and Caco-2 cells.
Pregabalin (PGB) is a novel drug under development for the treatment of epilepsy, neuropathic pain, fibromyalgia, and generalized anxiety disorder. In this study, we investigated PGB transport in rats, mammalian cell lines, and Xenopus laevis oocytes. In contrast to gabapentin (GBP), PGB absorption in rats showed unique linear pharmacokinetics. ⋯ In contrast, at clinically relevant concentrations, PGB seemed not to interact with GABA transport in GAT1, GAT2, and GAT3 cell lines, system y(+), b(0,+), B(0,+), and B(0) transport activities in Caco-2 and NBL-1 cells, and the b(0,+)-like transport activity in rBAT cRNA-injected X. laevis oocytes. Taken together, these results suggest that L-type transport is the major transport route for PGB and GBP uptake in mammalian cells. The differential affinity of PGB and GBP at L-type system leads to more concentrative accumulation of PGB than GBP, which may facilitate PGB transmembrane absorption in vivo.
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J. Pharmacol. Exp. Ther. · Jun 2005
Stilbazulenyl nitrone, a second-generation azulenyl nitrone antioxidant, confers enduring neuroprotection in experimental focal cerebral ischemia in the rat: neurobehavior, histopathology, and pharmacokinetics.
Stilbazulenyl nitrone (STAZN) is a potent lipophilic second-generation azulenyl nitrone antioxidant, which is highly neuroprotective in rodent models of cerebral ischemia and trauma. This study was conducted to establish whether the neuroprotection induced by STAZN persists with chronic survival and to characterize STAZN's pharmacokinetics. Physiologically regulated rats received a 2-h middle cerebral artery occlusion by intraluminal suture and were treated with either STAZN [four 0.6 mg/kg doses i.p. administered at 2 (i.e., onset of recirculation), 4, 24, and 48 h; n = 16] or dimethyl sulfoxide vehicle (n = 11). ⋯ STAZN tissue levels at 2 to 3 h were, on average, 2.5% of blood levels in forebrain, 56% in myocardium, and 41% in kidney. STAZN was concentrated in liver with initial concentrations averaging 5.2-fold above blood levels and a subsequent linear decline of 40% between 24 and 72 h. These results establish that STAZN confers enduring ischemic neuroprotection, has a long circulating half-life, and penetrates well into brain and other organs-characteristics favoring its potential therapeutic utility.
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J. Pharmacol. Exp. Ther. · Jun 2005
Comparative StudyComparison of the antinociceptive profiles of gabapentin and 3-methylgabapentin in rat models of acute and persistent pain: implications for mechanism of action.
The anticonvulsant gabapentin (GBP) has been shown effective for the treatment of neuropathic pain, although its mechanism of action remains unclear. A recent report has suggested that binding to the alpha(2)delta subunit of voltage-gated calcium channels contributes to its antinociceptive effect, based on the stereoselective efficacy of two analogs: (1S,3R)3-methylgabapentin (3-MeGBP) (IC(50) = 42 nM), which is effective in neuropathic pain models; and (1R,3R)3-MeGBP (IC(50) > 10,000 nM), which is ineffective (Field et al., 2000). The present study was designed to further examine the profiles of GBP and 3-MeGBP in rat models of acute and persistent pain. ⋯ Systemic (1S,3R)3-MeGBP, but not GBP or (1R,3R)3-MeGBP, also produced an antinociceptive effect in the warm water tail withdrawal test of acute pain. These data demonstrate that GBP and 3-MeGBP display different antinociceptive profiles, suggesting dissimilar mechanisms of antinociceptive action. Thus, the stereoselective efficacy of 3-MeGBP, presumably related to alpha(2)delta binding, likely does not completely account for the mechanism of action of GBP.
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J. Pharmacol. Exp. Ther. · Jun 2005
Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of buprenorphine and fentanyl in rats: role of receptor equilibration kinetics.
The objective of this investigation was to characterize the pharmacokinetic/pharmacodynamic correlation of buprenorphine and fentanyl for the antinociceptive effect in rats. Data on the time course of the antinociceptive effect following intravenous administration of buprenorphine or fentanyl was analyzed in conjunction with plasma concentrations by nonlinear mixed-effects analysis. For fentanyl, the pharmacokinetics was described on the basis of a two-compartment pharmacokinetic model. ⋯ The k(off) was 0.073 min(-1) (95% CI: 0.042-0.104 min(-1)) and k(on) was 0.023 ml/ng/min (95% CI: 0.013-0.033 ml/ng/min). Fentanyl binds instantaneously to the OP3 receptor because no reasonable values for k(on) and k(off) were obtained with the dynamical receptor model. In contrast to earlier reports in the literature, the findings of this study show that the rate-limiting step in the onset and offset of buprenorphine's antinociceptive effect is distribution to the brain.