To develop and validate an in vivo cocktail method for high-throughput phenotyping of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A, 12 healthy subjects received five probe drugs alone or simultaneously. The in vivo phenotyping index of CYP2C9, the ratio of 8 h urine concentration of losartan to its metabolite after a single administration of losartan, was not significantly different from that obtained using the five-drug cocktail. Similarly, the ratios of [omeprazole]/[5-hydroxyomeprazole] (CYP2C19) and [paraxanthine]/[caffeine] (CYP1A2) in 4 h plasma samples and the log ratio of [dextromethorphan]/[dextrorphan] (CYP2D6) in 8 h urine samples and the 4 h plasma concentrations of midazolam (CYP3A) after single administration or well-established three-drug cocktail of caffeine, omeprazole, and dextromethorphan were not significantly different from those after the new five-drug cocktail. In conclusion, the new five-drug cocktail regimen, named the "Inje cocktail," can be used as a tool to phenotype in vivo enzyme activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A with only 4 h blood sampling and 8 h urine collection following simultaneous administration of the five probe drugs.

To evaluate the association between the risk of chronic obstructive pulmonary disease (COPD) and exposure to vapors, gases, dusts, or fumes (VGDF), we conducted a meta-analysis of epidemiological studies. We searched for studies investigating the relationship between COPD and occupational exposure to VGDF in the adult population. The bibliographic search was conducted in databases (PubMed and Google Scholar). Eleven studies that met predetermined inclusion criteria were included in the meta-analysis. We calculated the pooled odds ratio (OR) with its 95% confidence interval (CI) of COPD for exposure to VGDF using a random-effects model. The presence of publication bias was explored. There was moderate heterogeneity among the included studies (I(2) = 54.3%). In a random-effects model meta-analysis, the pooled OR for exposure to VGDF was 1.43 for COPD (95% CI: 1.19-1.73) compared with no exposure to VGDF. Publication bias was not observed in this study. Our study suggests that exposure to VGDF is associated with a higher risk of COPD. Further prospective cohort studies are needed to confirm this association.

AimsTo evaluate the effects of three ABCG2 variants (Q141K, V12M and Q126X), which are known to have altered transport properties in vitro, on the disposition of lamivudine in healthy subjects. MethodsTo evaluate whether lamivudine is a substrate of ABCG2, intracellular accumulation and vectorial transport of 3 H-lamivudine were determined in MDCK-ABCG2 cells. The pharmacokinetic parameters of lamivudine were compared among subjects with four different ABCG2 genotypes, including wild type (seven subjects), K141/K141 (six subjects), Q126/Stop126 (four subjects) and M12/M12 (five subjects) after a single oral dose of 100 mg lamivudine. ResultsThe intracellular accumulation of lamivudine in MDCK-ABCG2 cells was significantly lower than that in MDCK-mock cells, but fumitremorgin C reversed the intracellular lamivudine concentration to that of MDCK-mock cells. The ABCG2-mediated transport of lamivudine was saturable and the values of Km and Vmax were 216.5 Ϯ 58 mm and 20.42 Ϯ 2.9 nmol h -1 per 10 6 cells, respectively. After lamivudine administration to healthy subjects, the AUC of lamivudine showed no difference among subjects with different ABCG2 genotypes; 2480 Ϯ 502, 2207 Ϯ 1019, 2422 Ϯ 239, 2552 Ϯ 698 ng h -1 ml -1 for wild type, K141/K141, Q126/Stop126 and M12/M12 genotype, respectively (P = 0.85). The estimated 95% confidence intervals for the mean difference between K141/K141, Q126/Stop126, M12/M12 and wild as reference were (-1053, 507), (-555, 439) and (-552, 696), respectively. No other pharmacokinetic parameters were estimated to be significantly different among four different ABCG2 genotypes tested. ConclusionsLamivudine appeared to be a substrate of ABCG2 in vitro, but the disposition of lamivudine was not significantly influenced by known in vitro functional variants of ABCG2, Q141K, V12M and Q126X in healthy subjects.

ABSTRACT:The objective of this study was to identify CYP3A4 variants in Koreans and to characterize their functional consequences in vitro and in vivo. Four single nucleotide polymorphisms were identified in 50 Koreans by direct DNA sequencing. In an additional genotyping using 248 subjects, CYP3A4*18 was confirmed as the most frequent coding variant in Koreans at 1.7%, and its frequency was similar to that of Asians, suggesting that CYP3A4*18 would be the highest coding variant in Asians. The recombinant CYP3A4.18 protein prepared in baculovirus expression system showed 67.4% lower V max and 1.8-fold higher K m for midazolam 1-hydroxylation compared with the wild type. The mean values of C max and area under the concentration curve (AUC) in the CYP3A4*1/*18 and CYP3A5*1/*3 subjects (n ‫؍‬ 8) were 63% and 32% higher than in CYP3A4*1/*1 and CYP3A5*1/*3 carriers (n ‫؍‬ 8), respectively. Although the in vitro assay exhibited a significant reduction of the enzyme activity for midazolam, the in vivo differences associated with the CYP3A4*1/*18 tend to be low (P < 0.07 in C max and P < 0.09 in AUC). In summary, the heterozygous CYP3A4*1/*18 does not appear to cause a significant change of midazolam disposition in vivo; however, the clinical relevance of CYP3A4*18/*18 remains to be evaluated.CYP3A is the most abundantly expressed subfamily of cytochrome P450 (P450) enzymes in the human liver (Shimada et al., 1994). The CYP3A enzymes are responsible for the metabolism of more than 50% of clinically used drugs (Komori et al., 1990;Guengerich, 1999;Lamba et al., 2002a). Four human CYP3A enzymes, CYP3A4, CYP3A5, CYP3A7, and CYP3A43, have been identified. CYP3A4 is regarded as the most dominant CYP3A enzyme in the liver and small intestine of humans. It has been reported that CYP3A4 expression shows large interindividual variation (Guengerich, 1999;Ozdemir et al., 2000;Lin et al., 2002). These variations can lead to different responses to human drugs that are substrates for CYP3A4. Because approximately 85% of this variability is attributed to genetic factors (Ozdemir et al., 2000), genetic analysis is needed to understand interindividual variability. To date, more than 39 allelic variants have been described (http://www.cypalleles.ki.se/cyp3a4.htm) (Dai et al., 2001;Eiselt et al., 2001;Kuehl et al., 2001;Lamba et al., 2002a;Fukushima-Uesaka et al., 2004). Among the CYP3A4 variants, alleles with nonsynonymous single nucleotide polymorphisms (SNPs), i.e., CYP3A4*2, *4, *5, *6, *17, and *18, have been shown to alter enzyme activity, compared with the wild type (Lee and Goldstein, 2005). Although some CYP3A SNPs exhibited an altered intrinsic clearance of CYP3A substrates in vitro, there have been few data explaining their meaningful influences on its substrate clearance in humans. The CYP3A4*1B promoter SNP has been extensively studied because of its role in transcriptional regulation in vitro. However, no significant change associated with CYP3A4*1B was observed in midazolam (MDZ) clearance (Wandel et al., 2000;Garcia-Martin...

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