The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes.
ABSTRACT The aim of this study was to search for a possible association between the variant allele of the single nucleotide polymorphisms A118G in the OPRM1 gene and C3435T and G2677T/A in the ABCB1 gene and altered antinociceptive effect and adverse drug reactions of oxycodone. Thirty-three healthy subjects exposed to experimental pain including electrical stimulation and the cold pressor test were included. A118G: We found that the variant G allele was associated with reduced antinociceptive effect as measured by pain tolerance thresholds to single electrical nerve stimulation (8% increase vs. 25% for the wild-type carriers, P = 0.007). C3435T: The carriers of the variant T allele generally had less adverse drug reactions on oxycodone than the carriers of the wild-type genotype. G2677T/A: The carriers of the variant T allele had a better antinociceptive effect of oxycodone than the carriers of the wild-type genotype in the cold pressor test (25% reduction vs. 15%, P = 0.015 in the discomfort rating and 25% reduction vs. 12%, P = 0.007 in the pain time AUC) and less adverse drug reactions. The combined wild-type genotype 3435CC-2677GG was associated with less antinociceptive effect of oxycodone in the discomfort rating of the cold pressor test (13% reduction vs. 23%, P = 0.019) and more severe adverse drug reactions than the carriers of the variant alleles. We found a moderate association between less antinociceptive effect of oxycodone and the variant allele of A118G. There was strong association between less adverse drug reactions of oxycodone and the variant alleles of C3435T and G2677T/A.
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ABSTRACT: The efficacy of drug therapy results from the complex interplay of multiple processes that govern drug disposition and response. Most studies to date have focused on the contribution of drug-metabolizing enzymes to the drug disposition process. However, over the past decade, it has become increasingly apparent that carrier-mediated processes, or transporters, also play critical roles in the overall disposition of numerous drugs in clinical use. In addition to their roles in xenobiotic transport, drug transporters often mediate important physiologic functions via transport of endogenous substrates such as amino acids, bile acids, and hormones that are critical for maintenance of normal homeostasis. In this review we focus on the emerging field of transporter proteins in relation to the drug disposition process, with particular emphasis on clinical implications of transporters to drug-drug interactions and subsequent development of adverse effects, interindividual variability in drug response, and human disease.Clinical Pharmacology & Therapeutics 10/2005; 78(3):260-77. · 6.85 Impact Factor
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ABSTRACT: There is considerable and unexplained individual variability in the morphine dose-effect relationship. The efflux pump P-glycoprotein regulates brain access and intestinal absorption of numerous drugs. Morphine is a P-glycoprotein substrate in vitro, and P-glycoprotein affects morphine brain access and pharmacodynamics in animals. However, the role of P-glycoprotein in human morphine disposition and clinical effects is unknown. This investigation tested the hypothesis that plasma concentrations and clinical effects of oral and intravenous morphine are greater after inhibition of intestinal and brain P-glycoprotein, with the P-glycoprotein inhibitor quinidine used as an in vivo probe. Two randomized, double-blind, placebo-controlled, balanced crossover studies were conducted in normal healthy volunteers after institutional review board-approved informed consent was obtained. In the first protocol, pupil diameter was evaluated after intravenous morphine administration (0.15 mg/kg), 1 hour after oral quinidine or placebo. In the second protocol, plasma morphine and glucuronide metabolite concentrations and pupil diameters were evaluated after oral morphine administration (30 mg), dosed 1 hour after oral quinidine (600 mg) or placebo. Quinidine had no effect on intravenous morphine effects (time to maximum miosis, maximum effect, or area under the curve [AUC] of miosis versus time). Quinidine increased the oral morphine maximum plasma concentration (31.8 +/- 14.9 ng/mL versus 16.9 +/- 7.4 ng/mL, P <.05) and AUC (65.1 +/- 21.5 versus 40.8 ng. h. mL(-1) +/- 14 ng. h. mL(-1), P <.05) but had no effect on elimination rate. Plasma morphine glucuronide concentrations were unchanged; however, the morphine glucuronide/morphine ratios were diminished by quinidine. Differences in oral morphine miosis (AUC, 16.8 +/- 9.3 mm. h versus 10.8 +/- 6.5 mm. h; P <.05) were commensurate with changes in plasma morphine concentration, and concentration-effect relationships were unchanged. Quinidine altered subjective self-assessments of oral but not intravenous morphine effects. Quinidine increased the absorption and plasma concentrations of oral morphine, suggesting that intestinal P-glycoprotein affected the absorption, bioavailability, and, hence, clinical effects of oral morphine. However, quinidine had no effect on morphine concentration-effect relationships, suggesting that if quinidine is an effective inhibitor of brain P-glycoprotein then P-glycoprotein did not appear to have a significant effect on brain access of morphine.Clinical Pharmacology & Therapeutics 01/2004; 74(6):543-54. · 6.85 Impact Factor
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ABSTRACT: P-glycoprotein, the gene product of MDR1, confers multidrug resistance against antineoplastic agents but also plays an important role in the bioavailability of common drugs in medical treatment. Various polymorphisms in the MDR1 gene were recently identified. A silent mutation in exon 26 (C3435T) was correlated with intestinal P-glycoprotein expression and oral bioavailability of digoxin. We wanted to establish easy-to-use and cost-effective genotyping assays for the major known MDR1 single nucleotide polymorphisms and study the allelic frequency distribution of the single nucleotide polymorphisms in a large sample of volunteers. In this study, the distribution of the major MDR1 alleles was determined in 461 white volunteers with the use of polymerase chain reaction and restriction fragment length polymorphism. Five amino acid exchanges were found with allelic frequencies of 11.2% for Asn21Asp and 5.5% for Ser400Asn. Strikingly, in exon 21 three variants were discovered at the same locus: 2677G (56.4%), 2677T (41.6%), and 2677A (1.9%), coding for 893Ala, Ser, or Thr. A novel missense Gln1107Pro mutation was found in two cases (0.2%). The highest frequencies were observed for intronic and silent polymorphisms; C3435T occurred in 53.9% of the subjects heterozygously, and 28.6% of individuals were homozygous carriers of 3435T/T with functionally restrained P-glycoprotein. This study provides the first analysis of MDR1 variant genotype distribution in a large sample of white subjects. It gives a basis for large-scale clinical investigations on the functional role of MDR1 allelic variants for bioavailability of a substantial number of drugs.Clinical Pharmacology & Therapeutics 04/2001; 69(3):169-74. · 6.85 Impact Factor