Tore Bjerregaard Stage

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.

The role of genetic variants in CYP2C8, LPIN1, PPARGC1A and PPARγ on the trough steady-state plasma concentrations of rosiglitazone and on glycosylated haemoglobin A1c in type 2 diabetes.

Objective The aim of this study was to examine the effect of single nucleotide polymorphisms in CYP2C8, LPIN1, PPARGC1A and PPAR&ggr; on rosiglitazone’s (i) trough steady-state plasma concentration (Css,min), (ii) on glycosylated haemoglobin A1c (HbA1c) and (iii) the risk of developing adverse events, mainly oedema, in patients with type 2 diabetes mellitus (T2D). Methods The data used in this study were obtained from the South Danish Diabetes Study including 371 T2D patients with a focus on the 187 patients who were treated with rosiglitazone. The study was a placebo-controlled, partly blinded and multicentre clinical trial. The Css,min of rosiglitazone and HbA1c was determined and the genotype of the patients was identified. Results The mean Css,min of rosiglitazone was 21.3 ng/ml (95% confidence interval 18.8; 24.2 ng/ml), with observations ranging from 1 to 296 ng/ml. Carriers of CYP2C8*3 (n=32) (rs10509681 and rs11572080) had a statistically significantly lower mean Css,min than wild types (n=106), and they also had a statistically significantly lower mean absolute difference in HbA1c during rosiglitazone treatment. Finally, the carriers of CYP2C8*3 had a lower odds ratio of developing oedema. Conclusion We showed that CYP2C8*3 was associated with lower plasma levels of rosiglitazone and hence a reduced therapeutic response but also a lower risk of developing oedema during treatment with rosiglitazone. Individualized treatment with rosiglitazone on the basis of the CYP2C8 genotype may therefore be possible.

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.

Generic switching of warfarin and risk of excessive anticoagulation: a Danish nationwide cohort study

Generic switching of warfarin was recently repealed in Denmark, as adverse drug reaction (ADR) reports suggested risk of excessive anticoagulation following switches from branded to generic warfarin. We investigated this putative association in a formalized pharmacoepidemiological analysis.

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.

The potential drug–drug interaction between proton pump inhibitors and warfarin

Proton pump inhibitors (PPIs) have been suggested to increase the effect of warfarin, and clinical guidelines recommend careful monitoring of international normalized ratio (INR) when initiating PPI among warfarin users. However, this drug–drug interaction is sparsely investigated in a clinical setting. The aim was to assess whether initiation of PPI treatment among users of warfarin leads to increased INR values.

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.

SearCh for humourIstic and Extravagant acroNyms and Thoroughly Inappropriate names For Important Clinical trials (SCIENTIFIC): qualitative and quantitative systematic study

Objectives To describe the development of acronym use across five major medical specialties and to evaluate the technical and aesthetic quality of the acronyms. Design Acronyms obtained through a literature search of Pubmed.gov followed by a standardised assessment of acronym quality (BEAUTY and CHEATING criteria). Participants Randomised controlled trials within psychiatry, rheumatology, pulmonary medicine, endocrinology, and cardiology published between 2000 and 2012. Main outcome measures Prevalence proportion of acronyms and composite quality score for acronyms over time. Results 14 965 publications were identified, of which 18.3% (n=2737) contained an acronym in the title. Acronym use was more common among cardiological studies than among the other four medical specialties (40% v 8-15% in 2012, P<0.001). Except for within cardiology, the prevalence of acronyms increased over time, with the average prevalence proportion among the remaining four specialties increasing from 4.0% to 12.4% from 2000 to 2012 (P<0.001). The median combined acronym quality score decreased significantly over the study period (P<0.001), from a median 9.25 in 2000 to 5.50 in 2012. Conclusion From 2000 to 2012 the prevalence of acronyms in trial reports increased, coinciding with a substantial decrease in the technical and aesthetic quality of the acronyms. Strict enforcement of current guidelines on acronym construction by journal editors is necessary to ensure the proper use of acronyms in the future.

Impaired Glucose Tolerance in Healthy Men Treated with St. John's Wort

The purpose of this study was to examine whether the over‐the‐counter herbal medicinal plant St. Johns wort affects glucose tolerance in healthy men. To do this, we included 10 healthy men who were examined by a 2‐hr oral glucose tolerance test on three occasions: A: baseline; B: after 21 days of treatment with St. Johns wort; and C: at least 6 weeks after the last capsule of St. Johns wort was ingested. Plasma glucose, serum insulin and C‐peptide levels were measured during an oral glucose tolerance test and used for estimation of area under the concentration–time curve (AUC) as well as indices of insulin sensitivity and insulin secretion. We found that treatment with St. Johns wort increased total and incremental glucose AUC and 2‐hr plasma glucose levels. Surprisingly, this effect was sustained and even further increased 6 weeks after the last capsule of St. Johns wort was taken. No effect on indices of insulin sensitivity was seen, but indices of insulin secretion were reduced even after adjustment for insulin sensitivity. In conclusion, this study indicates that long‐term treatment with St. Johns wort may impair glucose tolerance by reducing insulin secretion in young, healthy men. The unregulated use of this over‐the‐counter drug might be a risk factor for impaired glucose tolerance and type 2 diabetes.

Lack of genetic association between OCT1, ABCB1, and UGT2B7 variants and morphine pharmacokinetics

Aim A high inter‐individual variation in the pharmacokinetics and pharmacodynamics of morphine has been observed. Genetic polymorphisms in genes encoding the organic cation transporter isoform 1 (OCT1), the efflux transporter p‐glycoprotein (ABCB1), and the UDP‐glucuronosyltransferase‐2B7 (UGT2B7) may influence morphine pharmacokinetics and thus, also pharmacodynamics. The aim of this study was to evaluate the association between OCT1, ABCB1, and UGT2B7 variants, and morphine pharmacokinetics and ‐dynamics in healthy volunteers. Methods Pharmacokinetic and pharmacodynamic data were collected from a double‐blinded, randomized, crossover trial in 37 healthy subjects. Pharmacokinetic data were analyzed in NONMEM®, and the time‐concentration relationship of morphine, morphine‐3‐glucuronide, and morphine‐6‐glucuronide was parameterized as the transit compartment rate constant (ktr), clearance (CL), and volume of distribution (VD). The area under the plasma concentration‐time curve (AUC0–150 min) and the maximum plasma concentration (Cmax) were also calculated. Pharmacodynamic data were measured as pain tolerance thresholds to mechanical stimulation of the rectum and muscle, as well as tonic cold pain stimulation (“the cold pressor test” where hand was immersed in cold water). Six different single nucleotide polymorphisms in three different genes (OCT1 (n = 22), ABCB1 (n = 37), and UGT2B (n = 22)) were examined. Results Neither AUC0–150 min, ktr, CL, nor VD were associated with genetic variants in OCT1, ABCB1, and UGT2B7 (all P > 0.05). Similarly, the antinociceptive effects of morphine on rectal, muscle, and cold pressor tests were not associated with these genetic variants (all P > 0.05). Conclusions In this experimental study in healthy volunteers, we found no association between different genotypes of OCT1, ABCB1, and UGT2B7, and morphine pharmacokinetics and pharmacodynamics. Nonetheless, due to methodological limitations we cannot exclude that associations exist.