Rasmus Steen Pedersen

Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective O-demethylation and reduces the hypoalgesic effect of tramadol.

Tramadol hydrochloride (INN, tramadol) exerts its antinociceptive action through a monoaminergic effect mediated by the parent compound and an opioid effect mediated mainly by the O‐demethylated metabolite (+)‐M1. O‐demethylation is catalyzed by cytochrome P450 (CYP) 2D6. Paroxetine is a very potent inhibitor of CYP2D6. The objective of this study was to investigate the influence of paroxetine pretreatment on the biotransformation and the hypoalgesic effect of tramadol.

Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer

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>G (P=0.04).

The Hypoalgesic Effect of Oxycodone in Human Experimental Pain Models in Relation to the CYP2D6 Oxidation Polymorphism

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.

Tramadol as a New Probe for Cytochrome P450 2D6 Phenotyping: A Population Study

Polymorphic cytochrome P450 (CYP) 2D6 activity has been shown to be a determinant of the pharmacokinetics and pharmacodynamics of tramadol via hepatic phase I O‐demethylation of (+)‐tramadol to (+)‐O‐desmethyltramadol. Our objective was to investigate whether tramadol can be used as a probe for CYP2D6 phenotyping by determining the concordance between the 8‐hour tramadol and 12‐hour sparteine metabolic urinary ratios.

A gene-gene interaction between polymorphisms in the OCT2 and MATE1 genes influences the renal clearance of metformin.

Objective The aim of this study was to determine the association between the renal clearance (CLrenal) of metformin in healthy Caucasian volunteers and the single-nucleotide polymorphism (SNP) c.808G>T (rs316019) in OCT2 as well as the relevance of the gene–gene interactions between this SNP and (a) the promoter SNP g.-66T>C (rs2252281) in MATE1 and (b) the OCT1 reduced-function diplotypes. Methods Fifty healthy volunteers genotyped for the c.808G>T were enrolled in the study. The distribution was 25 GG, 20 GT, and 5 TT volunteers. The pharmacokinetics of a 500 mg single oral dose of metformin was studied. Results When analyzed alone, the c.808 (G>T) affected neither the CLrenal nor the secretory clearance (CLsec) of metformin. However, both CLrenal and CLsec were increased for the volunteers with minor alleles in c.808 (G>T) who were also homozygous for the reference variant g.-66T>C: CLrenal: GG, GT, and TT: 28.1, 34.5, and 44.8 l/h (P=0.004), respectively and CLsec: GG, GT, and TT: 21.4, 27.8, and 37.6 l/h (P=0.005), respectively. In the volunteers with minor alleles in c.808 (G>T) who were also heterozygous for g.-66T>C, both CLrenal and CLsec were found to be reduced (P<0.028) when compared with volunteers with minor alleles in c.808 (G>T) carrying the g.-66T>C reference genotype. Conclusion We report counteracting effects of the c.808 (G>T) and g.-66T>C on the renal elimination of metformin. When adjusted for the genetic variation g.-66T>C, our results suggest that c.808 (G>T) could have a dominant genotype to phenotype correlation.

Enantioselective HPLC method for quantitative determination of tramadol andO-desmethyltramadol in plasma and urine: Application to clinical studies

SummaryA sensitive, enantioselective high-performance liquid chromatographic method has been developed for the separation and individual quantitative determination of (+)-and (-)-tramadol and (+)- and (-)-O-desmethyltramadol (M1) in plasma and urine. Extraction from plasma and urine was performed by solid-phase extraction (SPE) on disposable butyl silica (100 mg) extraction cartridges. Separation of the enantiomers of tramadol and M1 was achieved on a Chiralpak AD column containing amylose tris-(3,5-dimethylphenylcarbamate) as chiral selector. The mobile phase was isohexane-ethanol-diethylamine, 97:2.8:0.1 (v/v). Quinidine was used as internal standard. The analytes were detected by use of fluorescence detection. The limit of quantification for tramadol and M1 as 5 nM in plasma and 25 nM in urine. Recoveries were approximately 90% for tramadol and M1 in both plasma and urine. Linearity was observed for both enantiomers of tramadol and M1 in both plasma (r2>0.999) and urine (r2>0.997). The intra and inter-day precision (CV) did not exceed 6.0%. The applicability of the method was demonstrated by means of two clinical studies—a pharmacokinetic study in which a healthy volunteer received 150 mg tramadol hydrochloride as a single oral dose and a study in which poor and extensive CYP2D6 metabolizers received 50 mg tramadol hydrochloride as a single oral dose.

Intake of St John's wort improves the glucose tolerance in healthy subjects who ingest metformin compared with metformin alone

AIMS Our objective was to investigate the steady-state pharmacokinetic and pharmacodynamic interaction between the antidepressive herbal medicine St Johns wort and the antidiabetic drug metformin. METHODS We performed an open cross-over study in 20 healthy male subjects, who received 1 g of metformin twice daily for 1 week with and without 21 days of preceding and concomitant treatment with St Johns wort. The pharmacokinetics of metformin was determined, and a 2 h oral glucose tolerance test was performed. RESULTS St Johns wort decreased the renal clearance of metformin but did not affect any other metformin pharmacokinetic parameter. The addition of St Johns wort decreased the area under the glucose concentration-time curve [702 (95% confidence interval, 643-761) vs. 629 min*mmol/L (95% confidence interval, 568-690), P = 0.003], and this effect was caused by a statistically significant increase in the acute insulin response. CONCLUSIONS St Johns wort improves glucose tolerance by enhancing insulin secretion independently of insulin sensitivity in healthy male subjects taking metformin.

Linkage disequilibrium between the CYP2C19*17 allele and other clinically important CYP2C allelic variants in a healthy Scandinavian population

In a previous study, in three Nordic populations [1], we determined the genotype and allele frequencies of the five most relevant CYP2C allelic variants (CYP2C8*3, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*17) and inferred the most likely haplotypes. CYP2C19*17 was found at a frequency of 15–22% and inferred to be a haplo-type marker not present together with the four defective alleles and thereby predicting efficient CYP2C substrate metabolism. Subsequently, Suarez-Kurtz [2] reported in populations of African descent a haplotype containing CYP2C19*17 and the reduced-activity allele CYP2C8*2, which opposes CYP2C19*17 as a marker for extensive CYP2C8 substrate metabolism. The present study was conducted in order to prospectively validate the previous findings and determine Nordic haplotypes containing the clinically important allelic variants CYP2C8*2 and CYP2C8*4. From a newly established biobank, 394 healthy Possible deviation from Hardy-Weinberg equilibrium was tested for each SNP with Pearsons chi-squared test with a level of significance of 5%, and the individual haplotypes were inferred by use of the software package PHASE version 2.1 [3, 4]. All seven CYP2C allelic variants were present in the Scandinavian population and tested to be in Hardy-Weinberg equilibrium. The allele frequencies with binomial confidence intervals were as follows: CYP2C8*3: 0.090 which were similar to our previous findings [1]. The allele frequencies of the two added CYP2C8 alleles were CYP2C8*2: 0.0051 (0.0014–0.013) and CYP2C8*4: 0.043 (0.030–0.060). As shown in Table 1, the apparent CYP2C wild-type haplotype was the most frequent (47%). The second most frequent haplotype (no. 2), with a frequency of 18%, was composed of CYP2C19*17 and apparent CYP2C8 and CYP2C9 wild-type alleles, and represented 97% (144 out of 148) of all predicted CYP2C19*17-containing haplotypes. Four rare CYP2C8*2 alleles were detected and inferred to be exclusively in haplotype with the remaining four CYP2C19*17 alleles. The 34 detected CYP2C8*4 alleles were inferred in two different CYP2C haplotypes: 16 CYP2C*4 alleles were inferred to represent a haplotype without any of the 6 other clinically important CYP2C SNPs (no. 8), and 18 CYP2C*4 alleles were inferred together with CYP2C19*2 (no. 7). The third haplotype composed of two CYP2C allelic variants (no. 4) also confirms previous findings [5] showing that CYP2C8*3 is present almost exclusively in haplotypes with CYP2C9*2 (70 of 71 alleles: 99%), and CYP2C9*2 appears most often in haplotypes with CYP2C8*3 (70 of 89 alleles: 79%). This study supports our previous findings that CYP2C19*17 is a frequent allelic variant in Scandinavia not in haplotype with the clinically …

A twin study of the trough plasma steady-state concentration of metformin

Objective The aim of this study was to determine the intrapair similarity in trough steady-state plasma concentrations of metformin in monozygotic and dizygotic twin pairs. Methods We included 16 twin pairs (eight monozygotic and eight dizygotic twin pairs) for this study after contacting 524 twin pairs. They were dosed with metformin to steady state (1 g twice daily) for 6 days and on day 7, the trough concentration of metformin was determined 12 h after the last dose. Results There was no strong intrapair similarity in trough steady-state plasma concentrations of metformin in either dizygotic or monozygotic twin pairs. Conclusion The trough steady-state plasma concentration of metformin does not appear to be tightly genetically regulated. The interpretation of this finding is limited by the small sample size.

CYP2C19*17 increases clopidogrel-mediated platelet inhibition but does not alter the pharmacokinetics of the active metabolite of clopidogrel†

The aim of the present study was to determine the impact of CYP2C19*17 on the pharmacokinetics and pharmacodynamics of the active metabolite of clopidogrel and the pharmacokinetics of proguanil. Thus, we conducted an open‐label two‐phase cross‐over study in 31 healthy male volunteers (11 CYP2C19*1/*1, 11 CYP2C19*1/*17 and nine CYP2C19*17/*17). In Phase A, the pharmacokinetics of the derivatized active metabolite of clopidogrel (CAMD) and platelet function were determined after administration of a single oral dose of 600 mg clopidogrel (Plavix; Sanofi‐Avensis, Horsholm, Denmark). In Phase B, the pharmacokinetics of proguanil and its metabolites cycloguanil and 4‐chlorphenylbiguanide (4‐CPB) were determined in 29 of 31 subjects after a single oral dose of 200 mg proguanil given as the combination drug Malarone (GlaxoSmithKline Pharma, Brondby, Denmark). Significant correlations were found between the area under the time–concentration curve (AUC0–∞) of CAMD and both the absolute ADP‐induced P2Y12 receptor‐activated platelet aggregation (r = −0.60, P = 0.0007) and the percentage inhibition of aggregation (r = 0.59, P = 0.0009). In addition, the CYP2C19*17/*17 and CYP2C19*1/*17 genotype groups had significantly higher percentage inhibition of platelet aggregation compared with the CYP2C19*1/*1 subjects (geometric mean percentage inhibition of 84%, 73% and 63%, respectively; P = 0.014). Neither the absolute ADP‐induced P2Y12 receptor‐activated platelet aggregation, exposure to CAMD nor the pharmacokinetic parameters of proguanil, cycloguanil and 4‐CPB exhibited any significant differences among the genotype groups. In conclusion, carriers of CYP2C19*17 exhibit higher percentage inhibition of platelet aggregation, but do not have significantly lower absolute P2Y12 receptor‐activated platelet aggregation or higher exposure to the active metabolite after a single oral administration of 600 mg clopidogrel.