The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Apr 1997
Pharmacogenetic determinants of codeine induction by rifampin: the impact on codeine's respiratory, psychomotor and miotic effects.
Our objective was to examine the effect of rifampin on codeine's pharmacodynamics and pharmacokinetics in extensive (EMs) and poor (PMs) metabolizers of debrisoquin. Fifteen healthy, nonsmoking males, 9 EMs and 6 PMs of debrisoquin, received codeine (120 mg) before and after rifampin (600 mg/d) for 3 weeks. The effects of codeine on respiration, pupil diameter and psychomotor performance were measured before codeine administration and during each study day. ⋯ In PMs, codeine's respiratory and psychomotor effects were unaltered by rifampin, but its pupillary effect was reduced. Codeine O-demethylation to produce morphine can be significantly induced by rifampin, but this induction is phenotypically determined. However, because (relative to base-line values) rifampin enhanced codeine N-demethylation more than codeine O-demethylation, morphine plasma concentrations were reduced-and hence codeine's pharmacodynamic effects were attenuated-in EMs of debrisoquin.
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J. Pharmacol. Exp. Ther. · Apr 1997
Clinical Trial Controlled Clinical TrialInhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability.
Enzymatic conversion of hydrocodone to hydromorphone is catalyzed by cytochrome P450 2D6, which is inactive in about 7% of Caucasians [poor metabolizers (PMs)] and can be inhibited by quinidine pretreatment in the remainder [extensive metabolizers (EMs)]. If hydromorphone, having a substantially higher mu-receptor affinity than hydrocodone, contributes importantly to the physiological and subjective effects of oral hydrocodone, then PMs should be less responsive to the same doses, and quinidine pretreatment should cause EMs to temporarily respond as PMs. ⋯ EMs and PMs were equally responsive to oral hydrocodone, and quinidine had no consistent effect on their responses, even though quinidine abolished the pre-existing metabolic differences in hydromorphone production, as measured in urine. These data suggest only a small role of hydromorphone in eliciting abuse-related responses to oral hydrocodone.
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J. Pharmacol. Exp. Ther. · Apr 1997
Antinociceptive effects of RB101, a complete inhibitor of enkephalin-catabolizing enzymes, are enhanced by a cholecystokinin type B receptor antagonist, as revealed by noxiously evoked spinal c-Fos expression in rats.
The effects of RB101, a complete inhibitor of enkephalin-catabolizing enzymes, alone or with a selective cholecystokinin (CCK)B receptor antagonist (CI988) or CCK(A) receptor antagonist (devazepide), on carrageenin-induced spinal c-Fos expression were investigated. Spinal c-Fos expression was observed 90 min after intraplantar carrageenin (6 mg/150 microl saline), with Fos-like-immunoreactive neurons preferentially located in the superficial laminae of the spinal dorsal horn. Intravenous RB101 (10, 20 and 40 mg/kg) dose-dependently reduced the number of superficial Fos-like-immunoreactive neurons (r2 = 0.739, P < .0001), with 63 +/- 2% (P < .0001) reduction for the highest dose. ⋯ These results show that RB101 dose-dependently decreases carrageenin-evoked spinal c-Fos expression. In addition, the effectiveness of RB101 can be revealed by preadministration of the CCK(B) receptor antagonist CI988. Considering the weak opioid side effects obtained with RB101 treatment and the strong increase of its effects by the CCK(B) receptor antagonist, this type of drug combination could have promising therapeutic application in the management of pain in humans.
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J. Pharmacol. Exp. Ther. · Apr 1997
Pharmacokinetics of G3139, a phosphorothioate oligodeoxynucleotide antisense to bcl-2, after intravenous administration or continuous subcutaneous infusion to mice.
An 18-mer full-phosphorothioate oligonucleotide with sequence antisense to the first six codons of the open reading frame of bcl-2 (G3139) has shown efficacy against the DoHH2 lymphoma implanted in severe combined immunodeficient mice. This study evaluated the pharmacokinetics of 35S-labeled G3139 in female BALB/c mice after single i.v. bolus administration or s.c. infusion for 1 week. After 100 microg i.v. bolus (approximately 5 mg/kg), the radioactivity was rapidly distributed and eliminated, with low blood levels 6 hr after administration. ⋯ After both routes of administration, most of the radioactivity was eliminated in the urine and to a lesser extent in the feces. Significantly more radioactivity was excreted in the urine after i.v. bolus, compared with s.c. infusion (33% on day 1 and 55% by day 3 for i.v. vs. 7.2% on day 1 and 12.9% by day 3 for s.c.). These data show that s.c. infusion resulted in less excretion and metabolism of the administered dose.