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Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking.

The metabolism of dextromethorphan, a drug used to probe genetically determined CYP2D6 activity has been investigated in vivo and in vitro. In vitro, kinetic parameters were determined in adult microsomes Km for the O-demethylation was much lower than for N-demethylation (7 versus 650 µM) but Vmaxwas comparable. Fetal liver microsomes actively catalysed the N-demethylation of dextromethorphan, with kinetic parameters (Vmaxand Km) quite similar in fetal and adult microsomal preparations while the O -demethylation did not exceed 5 of adult activity. In microsomes, the N-demethylation was inhibited by antibodies raised against CYP3A subfamily members although fetal microsomes were much less sensitive to immunoinhibition than adult microsomes. In vivo, urinary excretion of dextromethorphan and its three demethylated metabolites was examined in 15 5 adult volunteers and compared between extensive (n144, 92.9) and poor (n11, 7.1) metabolizers. The O-demethylation to dextrorphan is the rate-limiting step of metabolism. In 2D6 poor metabolizers, the N-demethylation to 3-methoxymorphinan is slightly higher than in 2D6 extensive metabolizers but does not compensate defective O -demethylation. The frequency distribution histograms of dextromethorphan/dextrorphan and 3-methoxymorphinan/3-hydroxymorphinan metabolic ratios appeared bimodally distributed, reflecting the participation of CYP2D6 in the O-demethylation reaction. They clearly differed from the random distribution of dextromethorphan/3-methoxymorphinan, and dextrorphan/3-hydroxymorphinan ratios among the population. These data clearly suggest that the N-demethylation of dextromethorphan is dependent on CYP3A and that both CYP2D6 and CYP3A are involved in the overall metabolism of dextromethorphan.

Bisoprolol is a selective β1-adrenoceptor antagonist devoid of partial agonist activity that can be used for treatment of chronic and acute myocardial ischemia. In this condition, it is important to demonstrate that a stable β-blocking effect at steady state can be predicted by a mathematical model determined by plasma concentration–effect relationship after an acute intravenous (i.v.) dose. This relation was studied in 10 healthy volunteers in a double-blind, randomized, cross-over, placebo-controlled study after a 5-min i.v. infusion of bisoprolol (5 mg) or placebo. Standardized exercise tests were recorded at different times for 48 h after infusion with simultaneous bisoprolol assay (high-performance liquid chromatography, HPLC) in plasma. After a 1-week interval, subjects received oral bisoprolol (10 mg once daily) for 5 days and exercise tests were repeated on day 5 before and 2, 3, and 4 h after dosing, with bisoprolol plasma level determined simultaneously. In the acute period, bisoprolol significantly decreased exercise heart rate (HR peak effect −20.5 ± 4) as compared with placebo. There was a direct relationship (no hysteresis) between β-blockade and plasma concentrations with a sigmoid (7 subjects) or a linear (3 subjects) best-fit model. After repeated bisoprolol administration, steady-state plasma levels were achieved and 88 of the observed decreases in exercise HR were within the 95 confidence interval (CI) for individual prediction. These data suggest that bisoprolol-induced β-blockade after repeated oral dosing can be predicted by single-test i.v. dose administration.

Encainide biotransformation to its active metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide cosegregates with the polymorphic oxidation of debrisoquine. Because quinidine has been reported recently to be a potent inhibitor of the enzyme responsible for this polymorphism (cytochrome P450db1), we tested the hypothesis that quinidine would selectively inhibit encainide metabolism and alter its effects in subjects with the extensive metabolism phenotype for debrisoquine oxidation. Seven subjects with the extensive and four subjects with the poor metabolism phenotype received encainide (60 mg p.o. and 4.5 mg of [14C]encainide i.v. administered simultaneously) alone and during chronic treatment with low dose quinidine (50 mg q 6 hr) in a randomized, crossover design. In extensive metabolizers, quinidine decreased encainide systemic clearance from 935 +/- 541 to 190 +/- 77 ml/min and encainide nonrenal clearance from 782 +/- 474 to 95 +/- 32 ml/min (both P less than .02). In this population, quinidine significantly increased encainide elimination half-life from 1.8 +/- 1.2 to 7.7 +/- 2.4 hr and fractional urinary recovery of unchanged encainide from 17.5 +/- 7.6 to 47.4 +/- 7.8% (both P less than .001). The extent to which quinidine altered these indices of encainide disposition was highly correlated with the metabolic ratio for debrisoquine oxidation (r = 0.62-0.95). Moreover, poor metabolism and QRS prolongation during encainide were blunted by addition of quinidine; the extent of quinidine-induced reversal of encainide-related ECG changes was also correlated with debrisoquine ratio (r = 0.91). In contrast, in poor metabolizers, quinidine did not change encainide disposition kinetics and neither encainide alone nor encainide plus quinidine significantly altered electrocardiographic intervals.(ABSTRACT TRUNCATED AT 250 WORDS)

The polymorphism of dextromethorphan and encainide metabolism is genetically determined and is related to the activity of hepatic CYP2D6. In order to examine the relations between CYP2D6 phenotype, genotype and the electrocardiographic response to the oral administration of encainide, 110 healthy subjects were studied. Metabolic ratios were calculated in urine after oral administration of 40 mg of dextromethorphan and in plasma obtained 2.5 h after oral administration of 50 mg of encainide. Encainide-induced electrocardiographic changes were measured 2.5 h after oral administration of the drug. Genotype was determined in 52 subjects. Results showed that phenotype, either extensive or poor metabolizer, for CYP2D6-dependent metabolism could be identified from the dextromethorphan metabolic ratio calculated in urine, from the encainide metabolic ratio calculated in plasma and from the genotype. However, despite the fact that the changes in atrioventricular (PR) and intraventricular (QRS) conduction times produced by encainide were different in extensive and poor metabolizer subjects and correlated with CYP2D6 activity, the electrocardiographic response was never 100% specific and sensitive for the identification of either phenotype. Moreover, genotypic identification of heterozygous and homozygous extensive metabolizer subjects did not predict CYP2D6 activity, as determined by dextromethorphan and encainide metabolic ratios, or encainide response, as determined by intraventricular and atrioventricular changes. Thus, CYP2D6 activity does not fully predict the electrocardiographic effects of encainide, and genotype, as determined in our study, cannot replace the determination of metabolic ratio in predicting CYP2D6 activity and encainide response in extensive metabolizer subjects.

A genetically determined pharmacokinetic and pharmacodynamic interaction between quinidine and single doses of encainide in healthy volunteers has previously been described. In subjects with the extensive metabolizer phenotype, quinidine blunted encainide-induced QRS prolongation (a marker of sodium channel block) because it impaired encainide biotransformation to the potent active metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide. Therefore, the purpose of this study was to test the hypothesis that quinidine would inhibit sodium channel block (and by inference arrhythmia suppression) during encainide therapy in patients with the extensive metabolizer phenotype. Surprisingly, however, in eight extensive metabolizer patients, the extent of QRS prolongation during chronic encainide therapy was unaltered by quinidine (139 +/- 21 vs. 139 +/- 22 msec) whereas arrhythmia suppression was enhanced (64 +/- 22 to 77 +/- 19%; P = .05). Plasma concentration data demonstrated that although encainide metabolism to ODE was partially impaired by quinidine, subsequent 3-methoxy-O-desmethyl encainide formation from ODE was virtually completely inhibited; thus steady-state plasma ODE remained unchanged whereas plasma encainide increased 10-fold (21 +/- 30 to 240 +/- 118 ng/ml; P less than .05). In contrast, no changes in disposition or in pharmacodynamics were observed in two poor metabolizers. It is concluded that the effect of this drug interaction in patients is determined by differential sensitivities to inhibition by quinidine of encainide O-demethylation and subsequent ODE 3-methoxylation. Evaluation of potential drug interactions should include assessment of possible genetic factors as well as of steady-state effects.

Troleandomycin, a macrolide antibiotic, has been shown to be demethylated and oxidized into a metabolite which forms an inactive complex with the iron(II) of cytochrome P-450. The role of glutathione in the metabolism of troleandomycin was investigated. Administration of troleandomycin (1 mmol X kg-1 p.o.) decreased the concentration of glutathione in the liver. The depletion of glutathione was increased in rats pretreated with phenobarbital and decreased in rats pretreated with CoCl2. In vitro, an inverse relationship was found between the concentration of glutathione in the incubation mixture and the appearance of the cytochrome P-450-troleandomycin metabolite complex. Glutathione, however, did not inhibit the demethylation of troleandomycin and did not destroy the cytochrome P-450-troleandomycin metabolite complex. The in vitro protective effect of glutathione was reproduced by cysteine but not by glycine. In vivo, decreasing the concentration of glutathione in the liver by food deprivation or by the administration of diethylmaleate increased the formation of the cytochrome P-450-troleandomycin metabolite complex. These results indicate that glutathione is depleted by a troleandomycin metabolite in vivo, whereas glutathione protects against the formation of the inactive cytochrome P-450-troleandomycin metabolite complex in vitro and in vivo.

Dabrafenib (D) and trametinib (T) improved survival in patients with BRAFV600mutmelanoma. High plasma concentration of D (PCD) is weakly associated with adverse events (AE). We investigated the relationship between PCD/T and tumour control or AE.

La repolarisation ventriculaire, mesurée par le QT, est influencée par les hormones sexuelles : l’estradiol l’allonge, la testostérone la raccourcit. Un QTc allongé (QTc-L) prédispose au risque de torsades-de-pointes (TdP), arythmies ventriculaires conduisant à la mort subite. Les modulateurs sélectifs des récepteurs aux estrogènes (SERM) ont des propriétés estrogéniques et anti-estrogéniques tissu-dépendant tandis que les anti-aromatase (AA) inhibent l’aromatisation de testostérone en estrogènes, entraînant une diminution du taux d’estradiol. Les effets de ces 2 classes médicamenteuses sur le risque de QTc-L et de TdP sont inconnus.

La fraction d’éjection ventriculaire gauche (FEVG) et les valeurs absolues du strain longitudinal global(GLS) sont plus basses chez les hommes que chez les femmes. Nous rapportons ici l’influence du statut hormonal sur la fonction du VG systolique chez les sujets sains et les patients atteints d’hyperplasie surrénale congénitale (HCS).

L’association D+T est un traitement majeur des mélanomes avancés mutés BRAFV600 avec un risque d’échappement et d’EI. Nous avons recherché un lien entre concentrations plasmatiques de D et T (CPD/T) avec la réponse tumorale et les EI.

La repolarisation ventriculaire, mesurée par l’intervalle QT (QTc), est influencée par les hormones sexuelles. La testostérone est connue pour raccourcir l’intervalle QT. Un QTc allongé prédispose au risque de torsades de pointes (TdP), pouvant conduire à la mort subite. Nous avons étudié l’effet de l’hypogonadisme et des traitements antiandrogènes sur le QTc et le risque de TdP chez l’homme.

Les médicaments à visée cardiovasculaire, tels les antiagrégants ou les antihypertenseurs, sont utilisés de façon large et beaucoup d’entre eux diminuent la morbidité et la mortalité cardiovasculaires. Néanmoins, des études controversées suggèrent, en particulier pour les antihypertenseurs, que ceux-ci pourraient augmenter le risque de cancer.

Drug interactions involving macrolides have been mainly reported in subjects receiving troleandomycin and in a few receiving erythromycin derivatives. In rats and in humans, troleandomycin, erythromycin and erythromycin derivatives induce microsomal enzymes; the induced isozymes of cytochrome P-450 have a high activity for these macrolides but a poor activity with several other substrates. These isozymes actively demethylate and oxidize these macrolides into nitrosoalkanes which form stable, inactive complexes with the iron of cytochrome P-450. Eventually, the oxidative metabolism of other drugs may be decreased. These effects are marked after administration of troleandomycin, moderate after administration of erythromycin derivatives and absent (or negligible) after administration of spiramycin, josamycin or midecamycin. A second adverse effect of the administration of troleandomycin or erythromycin derivatives is the possible occurrence of hepatitis. Mild hepatic dysfunction is fairly frequent and may be toxic in type. In contrast, jaundice is common, is frequently associated with hypersensitivity, and promptly recurs when the drug is readministered. Troleandomycin and erythromycin derivatives, which form nitrosoalkanes, produce hepatitis, whereas josamycin, midecamycin and spiramycin, which do not form cytochrome P-450-nitrosoalkane complexes, rarely, if ever, produce hepatitis. Nitrosoalkanes are unstable intermediates which react with glutathione but also with cysteine and might covalently bind to the SH-groups of proteins. The following mechanism might be proposed as a hypothetical attempt to link up these various observations. The macrolide (or its reactive metabolite) may have discrete toxicity; in several subjects, this may produce minor liver lesions and a mildly raised aminotransferase activity. Necrosis of a few hepatocytes may release into the circulation plasma membrane proteins altered by the covalent binding of metabolites. Such modified liver antigens may be recognized as foreign and may trigger, in an exceptional subject, an immunoallergic type of clinical hepatitis.