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Aims Our objective was to investigate the steady-state pharmacokinetic and pharmacodynamic interaction between the antidepressive herbal medicine St John's wort and the antidiabetic drug metformin.

Udgivelsesdato: 2009-Apr Oxycodone is O-demethylated by CYP2D6 to oxymorphone which is a potent micro-receptor agonist. The CYP2D6 oxidation polymorphism divides the Caucasian population in two phenotypes: approximately 8% with no enzyme activity, poor metabolizers (PM) and the remainder with preserved CYP2D6 activity, extensive metabolizers (EM). The objective of the study was to determine if the analgesic effect of oxycodone in human experimental pain depends on its metabolism to oxymorphone. The analgesic effect of oxycodone was evaluated in a randomized, placebo-controlled, double-blinded, crossover experiment including 33 (16 EM and 17 PM) healthy volunteers. Pain tests were performed before and 1, 2, 3 and 4 hr after medication and included pain detection and tolerance thresholds to single electrical sural nerve stimulation, pain summation threshold to repetitive electrical sural nerve stimulation and the cold pressor test with rating of discomfort and pain-time area under curve (AUC(0-2 min.)). For single sural nerve stimulation, there was a less pronounced increase in thresholds on oxycodone in pain detection (9% vs. 20%, P = 0.02, a difference of 11%, CI: 2%-20%) and pain tolerance thresholds (15% vs. 26%, P = 0.037, a difference of 10%, CI: 1%-20%) for PM compared with EM. In the cold pressor test, there was less reduction in pain AUC on oxycodone for PM compared with EM (14% vs. 26%, P = 0.012, a difference of 12%, CI: 3%-22%). The plasma oxymorphone/oxycodone ratio was significantly lower in PM compared with EM (P < 0.001). Oxycodone analgesia seems to depend both on oxycodone itself and its metabolite oxymorphone.

ObjectiveThe aim of this study was to determine the intrapair similarity in trough steady-state plasma concentrations of metformin in monozygotic and dizygotic twin pairs.MethodsWe included 16 twin pairs (eight monozygotic and eight dizygotic twin pairs) for this study after contacting 524 twin pair

The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h(-1) (range 176-726 l h(-1)). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P = 0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P = 0.04) and ABCC1 g.7356253C andgt; G (P = 0.04). Original Publication:T K Bergmann, C Brasch-Andersen, Henrik Green, M Mirza, R S Pedersen, F Nielsen, K Skougaard, J Wihl, N Keldsen, P Damkier, L E Friberg, Curt Peterson, W Vach, M O Karlsson and K Brosen, Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer, 2011, PHARMACOGENOMICS JOURNAL, (11), 2, 113-120.http://dx.doi.org/10.1038/tpj.2010.19Copyright: Nature Publishing Grouphttp://npg.nature.com/

Cytochrome P4502C19 (CYP2C19) is an important drug-metabolizing enzyme involved in the biotransformation of, for example, proton pump inhibitors and antidepressants. Several in vivo studies have shown that the CYP2C19 activity is inhibited by oral contraceptives, which can cause important drug interactions. The underlying molecular mechanism has been suggested to be competitive inhibition. However, the results presented here indicate that estradiol derivatives down-regulate CYP2C19 expression via estrogen receptor (ER)alpha, which interacts with the newly identified ER-binding half site [estrogen response element (ERE)] at the position -151/-147 in the CYP2C19 promoter. In gene reporter experiments in Huh-7 hepatoma cells, the activity of the luciferase construct carrying a 1.6-kb long CYP2C19 promoter fragment cotransfected with ER alpha was down-regulated upon treatment with 17 beta-estradiol (EE) or 17 alpha-ethinylestradiol (ETE) at half-maximum concentrations of 10(-7) and 10(-8) M, respectively. Mutations introduced into the ERE half site -151/-147 significantly inhibited these ligand-dependent effects. Electrophoretic mobility shift assays and quantitative chromatin immunoprecipitation experiments revealed that estrogen receptor alpha binds to this element. A significant suppression of CYP2C19 transcription by female sex steroids was confirmed by reverse transcription polymerase chain reaction after hormonal treatment of human hepatocytes. Inhibition experiments using a stable human embryonic kidney 293 CYP2C19 cell line revealed competitive inhibition at much higher concentrations of EE and ETE compared with those required for transcriptional inhibition. These results indicate that both EE and ETE inhibit CYP2C19 expression via an ER alpha-dependent regulatory pathway, thus providing a new insight into the molecular mechanism behind the inhibitory effect of oral contraceptives on CYP2C19 activity. Hjarnfonden, Torsten och Ragnar Soderbergs Stiftelser [MT22/08]; Swedish Research Council [K2008-66X05949-28-3]; Danish Agency of Science, Technology and Innovation; Lundbeck Foundation; Portuguese Foundation for Science and Technology [SFRH/BPD/34152/2006]

To determine the distribution of clinically important CYP2C genotypes and allele frequencies in healthy Nordic populations with special focus on linkage disequilibrium. A total of 896 healthy subjects from three Nordic populations (Danish, Faroese, and Norwegian) were genotyped for five frequent and clinically important CYP2C allelic variants: the defective CYP2C8*3, CYP2C9*2, CYP2C9*3, and CYP2C19*2 alleles, and the CYP2C19*17 allele that causes rapid drug metabolism. Linkage disequilibrium was evaluated and CYP2C haplotypes were inferred in the entire population. Ten CYP2C haplotypes were inferred, the most frequent of which (49%) was the CYP2C wildtype haplotype carrying CYP2C8*1, CYP2C9*1, and CYP2C19*1. The second most frequent haplotype (19%) is composed of CYP2C19*17, CYP2C8*1, and CYP2C9*1. This predicted haplotype accounts for 99.7% of the CYP2C19*17 alleles found in the 896 subjects. CYP2C19*17 is a frequent genetic variant in Nordic populations that exists in strong linkage disequilibrium with wildtype CYP2C8*1 and CYP2C9*1 alleles, which effectively makes it a determinant for a haplotype exhibiting an efficient CYP2C substrate metabolism.

CYP2C9 is an important drug-metabolizing enzyme that metabolizes, e. g., warfarin, antidiabetics, and antiphlogistics. However, the endogenous regulation of this enzyme is largely unknown. In this study, we examined the role of GATA transcription factors in the gene expression of CYP2C9. We investigated four putative GATA binding sites within the first 200 base pairs of CYP2C9 promoter at the positions I: -173/-170, II: -167/-164, III: -118/ -115, and IV: -106/-103. Luciferase activity driven by a wildtype CYP2C9 promoter construct was strongly up-regulated in Huh-7 cells upon cotransfection with expression plasmids for GATA-2 and GATA-4, whereas mutations introduced into GATA binding site III or I and II reduced this induction to a significant extent. Electrophoretic mobility shift assays revealed specific binding of GATA-4 and GATA-6 to the oligonucleotides containing GATA binding sites I and II. Furthermore, the association of GATA-4 with CYP2C9 promoter was confirmed by chromatin immunoprecipitation assays in HepG2 cells. Taken together, these data strongly suggest an involvement of liver-specific transcription factor GATA-4 in the transcriptional regulation of CYP2C9. Swedish Research Council; Stockholm County Council; Danish Agency of Science, Technology and Innovation; Lundbeck Foundation; Portuguese Foundation for Science and Technology [SFRH/BPD/34152/2006 IBB/CBME]

PURPOSE: To investigate paroxetine's putative dose-dependent impact on pupil reaction and inhibition of the O-demethylation of tramadol.METHODS: Twelve healthy CYP2D6 extensive metabolizers participated in this double-blinded randomized five-way placebo controlled cross-over study; they received placebo, 10, 20, 30, and 50 mg paroxetine as single oral doses at bedtime. Next morning the pupil was measured followed by oral intake of 50 mg of tramadol, and urine was collected for 8 h. Three hours after ingestion of tramadol a second measurement of the pupil was performed. Enantioselective urine concentrations of (+/-)-tramadol and (+/-)-O-desmethyltramadol (M1) were determined.RESULTS: With placebo, the median maximum pupil diameter was 6.43 mm (range 5.45-7.75 mm) before tramadol and 6.22 mm (4.35-7.65 mm) after 50 mg of tramadol (P = 0.4935). Paroxetine resulted in a statistically significant, dose-dependent dilatation of the pupil with a geometric mean difference of 1.17 (95% CI 1.10-1.24) after ingestion of 50 mg paroxetine (P < 0.001). Likewise, a reduction in the relative constriction amplitude with a geometric mean difference of 0.81 (95% CI 0.71-0.92) (P < 0.001) was seen. A dose-dependent inhibition of the metabolism of tramadol by an increase in the two urinary metabolic ratios (+)-tramadol / (+)-M1 [geometric mean difference 9.09, 95% CI 5.60-14.73 (P < 0.001)] and (-)-M1 / (+)-M1 [geometric mean difference 2.84, 95% CI 2.15-3.77 (P < 0.001)] was also observed.CONCLUSIONS: Paroxetine is a dose-dependent dilator of the pupil and as expected a dose-dependent inhibitor of (+)-tramadol's O-demethylation.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The only existing study of CYP2C19*17-associated alterations in drug pharmacokinetics was retrospective and compared probe drug metabolic ratios. • The CYP2C19*17 allele had been associated with a two- and fourfold decrease in omeprazole and S/R-mephenytoin metabolic ratios. WHAT THIS STUDY ADDS • This study characterized the single-dose pharmacokinetics of omeprazole, along with the 5-hydroxy and sulphone metabolites, in CYP2C19*17/*17 and CYP2C19*1/*1 subjects. • The observed differences in omeprazole AUC∞ suggest that the CYP2C19*17 allele is an important explanatory factor behind individual cases of therapeutic failure. AIMS To investigate the influence of the CYP2C19*17 allele on the pharmacokinetics of omeprazole, a commonly used CYP2C19 probe drug, in healthy volunteers. METHODS In a single-dose pharmacokinetic study, 17 healthy White volunteers genotyped as either CYP2C19*17/*17 or CYP2C19*1/*1 received an oral dose of 40 mg of omeprazole. Plasma was sampled for up to 10 h postdose, followed by quantification of omeprazole, 5-hydroxy omeprazole and omeprazole sulphone by high-performance liquid chromatography. RESULTS The mean omeprazole AUC∞ of 1973 h nmol l−1 in CYP2C19*17/*17 subjects was 2.1-fold lower [95% confidence interval (CI) 1.1, 3.3] than in CYP2C19*1/*1 subjects (4151 h nmol l−1, P = 0.04). A similar trend was observed for the sulphone metabolite with the CYP2C19*17/*17 group having a mean AUC∞ of 1083 h nmol l−1, 3.1-fold lower (95% CI 1.2, 5.5) than the CYP2C19*1/*1 group (3343 h nmol l−1, P = 0.03). A pronounced correlation (r2 = 0.95, P

AIMS: To determine the effect of CYP2C8 genotype and of fluvoxamine on the pharmacokinetics of rosiglitazone.METHODS: Twenty-three healthy subjects with the following genotypes were included in a two-phase, open-label, cross-over trial: CYP2C8*3/ *3 (n = 3), CYP2C8*1/ *3 (n = 10) and CYP2C8*1/ *1 (n = 10). In Phase A, the subjects were given 4 mg rosiglitazone as a single oral dose. In Phase B, the subjects were treated with multiple oral doses of 50 mg fluvoxamine maleate for 3 days prior to the single oral administration of 4 mg rosiglitazone. Plasma concentrations of rosiglitazone and relative amounts of N-desmethylrosiglitazone were measured in both phases for 24 h after drug administration.RESULTS: The pharmacokinetics of rosiglitazone and N-desmethylrosiglitazone were not significantly different between the CYP2C8 genotypic groups. Fluvoxamine caused a statistically significant (P = 0.0066) increase in the AUC(0-infinity) of rosiglitazone, with a geometric mean ratio of 1.21 [95% confidence interval (CI) 1.06-1.39]. The elimination half-life (t(1/2)) was also significantly higher (P = 0.0203) with a geometric mean ratio of 1.38 [95% CI 1.06-1.79]. The coadministration of fluvoxamine had no influence on the pharmacokinetics of N-desmethylrosiglitazone.CONCLUSION: The importance of the CYP2C8*3 mutation in the in vivo metabolism of rosiglitazone could not be confirmed. Fluvoxamine increased the AUC(0-infinity) and t(1/2) of rosiglitazone moderately and hence may be a weak inhibitor of CYP2C8.

The human CYP2C is a subfamily of P450 enzymes that metabolize approximately 20% of clinically used drugs (Goldstein 2001). The four members of the subfamily are: CYP2C8, CYP2C9, CYP2C18 and CYP2C19. CYP2C9 is an enzyme of major importance in human drug metabolism. Substrates for CYP2C9 include phenytoin (Banpai et al. 1996), S-warfarin (Rettie et al. 1992), acenocoumarol (Verstuyft et al. 2003a), losartan (Stearns et al. 1995), tolbutamide (Miners & Birkett 1996), glipizide (Kidd et al. 1999), fluvastatin (Kirchheiner et al. 2003) and some NSAIDs (Miners & Birkett 1998). Six different human CYP2C9 cDNA sequences have been reported to make the enzyme polymorphic (Stubbins et al. 1996). Since the wildtype CYP2C9*1 and the single nucleotide polymorphisms CYP2C9*2 and CYP2C9*3 were discovered first, they have undergone more thorough investigation showing that the allelic variants CYP2C9*2 and CYP2C9*3 encode enzymes with decreased substrate turnover (Craig et al. 2002; Kirchheiner et al. 2002; Shon et al. 2002). The CYP2C9*2 allele, which is derived from a C430»T single nucleotide polymorphism in exon 3, encodes the Arg144»Cys substitution, whereas a A1075»C single nucleotide polymorphism in exon 7 results in the substitution Ile359»Leu for CYP2C9*3 (Stubbins et al. 1996). The allele frequencies of CYP2C9*1, CYP2C9*2 and CYP2C9*3 and the genotype frequencies of CYP2C9*1/*1, CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/ *3 and CYP2C9*3/*3 for a Nordic population in Denmark were determined. Two hundred seventy-six healthy Nordic (mainly Danish) volunteers of Caucasian origin were enrolled in the study. The 154 males and 122 females aged 19–42 were primarily students at the University of Southern Denmark. The pro

To study the use of size, maturation and CYP2D6 genotype score as predictors of i.v. tramadol (M) disposition throughout human life, published observations were pooled [1-6].

BackgroundToxicity and therapeutic effects of paclitaxel vary greatly between patients and remain a clinically relevant problem with regard to the handling of dose delay/reduction or termination of treatment. We investigated the notion that single nucleotide polymorphisms (SNPs) in CYP2C8 could be partly responsible for this variation. Paclitaxel is mainly metabolized by CYP2C8; SNPs have been investigated in this context before but conclusions are still lacking. We present a prospective study of paclitaxel clearance (CL) in 93 Caucasian females with epithelial ovarian cancer with regard to the CYP2C8 *1b, *1c, *3 and *4 genotypes.Material and methodsAll patients were diagnosed with primary ovarian/peritoneal cancer and received 175mg/m2 paclitaxel over 3 hrs plus carboplatin (AUC5-6) q3w. All patients gave written and verbal consent. The study was approved by ethics committees in Denmark and Sweden. Blood was sampled at 3hrs, 5-8 hrs and 18-24hrs after start of infusion. Total plasma paclitaxel was quantified using HPLC. CremophorEL® (CrEL) was determined as described by Sparreboom et al.1998. CL of unbound paclitaxel was estimated using total concentrations, CrEL and other parameters in the model described by Henningsson et al.2003 using NONMEM VI. Genotypes were determined using Pyrosequencing. Genotypes were in HW equilibrium, except *1b (p=0.01).ResultsThe PK model predicted the data well. The CL of unbound paclitaxel was lower for patients with the CYP2C8*3 and *4 variants (pCYP2C8variantNPaclitaxel CL geometric mean (l/h)95% c.iP-value(T-test of log transformed CL)Wt/Wt49395.0[370.3;421.4] Wt/*1b + *1b/*1b(n=1)44374.5[348.8;402.2]0.267Wt/Wt69382.4[362.1;404.0] Wt/*1c24393.1[355.4;434.8]0.617Wt/Wt74394.7[375.2;415.3] Wt/*319350.0[310.0;395.3]0.041*Wt/Wt86390.9[372.1;410.7] Wt/*47320.8[281.7;365.3]0.028*Note: for the one patient carrying both the *3 and *4 variant CL was 269.7 l/hConclusionsThis study implies reduced elimination of paclitaxel in Caucasian female patients with the CYP2C8*3 and *4 genotypes. This confirms several in vitro studies and pilot studies but is different to Henningsson et al 2005 and Marsh et al 2006 which could be explained by differences in dose ranges, infusion times and/or related to gender. The finding is important in terms of understanding inter individual variability of paclitaxel pharmacokinetics and might in the future provide useful information for individualized chemotherapy.