Assessment of individual CYP2D6 activity in extensive metabolizers with renal failure: comparison of sparteine and dextromethorphan.

Objectives: To examine whether the variability of CYP2D6 activity in patients with chronic renal failure can be assessed, particularly among subjects with the extensive metabolizer phenotype, by use of standard in vivo indexes of CYP2D6 activity derived from oral administration of dextromethorphan and sparteine.

Methods: A single 100 mg oral dose of sparteine and a single 40 mg oral dose of dextromethorphan were administered on two occasions to 12 patients with chronic renal failure (creatinine clearance ranging from 20 to 70 ml/min) and 12 age- and sex-matched healthy subjects. Sparteine clearances, sparteine metabolic ratio, and urinary recovery of dextrorphan were calculated.

Systematic screening for pharmacokinetic interactions during drug development.

The possible involvement of a new chemical entity in pharmacokinetic drug interactions is an important safety issue. Not all relevant drug combinations for evaluation of the interactive potential of a new drug can be examined. Therefore, experiments should be selected to provide information which is valid not only for the interaction investigated, but which can be extrapolated to other comedications.

Prediction of CYP2D6-mediated polymorphic drug metabolism (sparteine type) based on in vitro investigations.

Discovery of genetic polymorphism in drug metabolism has contributed a great deal to understanding the variability in dose-concentration relationships introduced by genetic factors, thereby elucidating the mechanisms responsible for unexpected drug reactions. This knowledge should find its way into clinical practice in order to make therapy more efficient and safe. Moreover, genetic factors in drug metabolism should be taken into account during drug development.

Characterization of the cytochrome P450 involved in side-chain oxidation of cyclophosphamide in humans.

Objective: Cyclophosphamide (CP) is an antineoplastic prodrug which requires bioactivation (4-hydroxylation) by the cytochrome P450 (CYP) enzymes in human liver. In parallel, P450-mediated side-chain oxidation (N-dealkylation) leads to the formation of the non-alkylating dechloroethylcyclophosphamide (DCI-CP) and chloroacetaldehyde, the latter being a potential neurotoxic agent. The enzyme responsible for side-chain oxidation has not been identified yet.

Immunohistochemical assessment of human microsomal epoxide hydrolase in primary and secondary liver neoplasm: a quantitative approach.

1. Epoxide hydrolases form an enzyme family involved in the metabolism of a variety of xenobiotics including cytostatic drugs and carcinogens. Whether human microsomal epoxide hydrolase--one of the main members of the epoxide hydrolase family--is expressed in neoplasia of the liver has been the subject of a controversial discussion.

Expression of cytochrome P 450 3A enzymes in human lung: a combined RT-PCR and immunohistochemical analysis of normal tissue and lung tumours.

We have previously demonstrated expression of cytochrome P 450 3A (CYP3A) protein in pulmonary carcinomas and surrounding normal tissue, using immunohistochemistry. These results suggested that different CYP3A enzymes may be expressed in normal and tumour tissue. Therefore, the aim of the present study was to identify specific CYP3A enzymes expressed in normal human lung and lung tumours.

Cytochromes of the P450 2C subfamily are the major enzymes involved in the O-demethylation of verapamil in humans.

The calcium channel blocker verapamil [2,8-bis-(3,4-dimethoxyphenyl)-6-methyl-2-isopropyl-6-azaoctanitrile+ ++] undergoes extensive biotransformation in man. We have previously demonstrated cytochrome P450 (CYP) 3A4 and 1A2 to be the enzymes responsible for verapamil N-dealkylation (formation of D-617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile], and verapamil N-demethylation (formation of norverapamil [2,8-bis-(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile]), while there was no involvement of CYP3A4 and CYP1A2 in the third initial metabolic step of verapamil, which is verapamil O-demethylation. This pathway yields formation of D-703 [2-(4-hydroxy-3-methoxyphenyl)-8-(3,4-dimethoxyphenyl)-6-methyl-2-isopro pyl-6-azaoctanitrile] and D-702 [2-(3,4-dimethoxyphenyl)-8-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-isopro pyl-6-azaoctanitrile].

The role of human cytochrome P450 enzymes in the metabolism of anticancer agents: implications for drug interactions.

1. Little information is available about the pharmacokinetic interactions of anticancer drugs in man. However, clinically significant drug interactions do occur in cancer chemotherapy, and it is likely that important interactions have not been recognized.

Direct gas chromatographic determination of dechloroethylcyclophosphamide following microsomal incubation of cyclophosphamide.

A method for the sensitive determination of dechloroethylcylclophosphamide (3-DCl) in microsomal incubation mixtures was developed. 3-DCl, a side-chain oxidation product of cyclophosphamide (CP), was isolated by extraction with acetic acid ethyl ester following solid-phase extraction on C8 cartridges. Quantification of the metabolite was performed by direct capillary gas chromatography with a nitrogen-phosphorus detector without prior derivatization.

In vitro characterization of cytochrome P450 catalysed metabolism of the antiemetic tropisetron.

The new 5-hydroxytryptamine type 3 (5HT3) receptor antagonist tropisetron is used in the treatment of chemotherapy-related nausea. The drug is extensively metabolized in man, with the enzymes involved in tropisetron biotransformation being unknown. Identification of these enzymes would make it possible to predict both interindividual variability in plasma concentrations and metabolic interaction potential.

"It's the genes, stupid". Molecular bases and clinical consequences of genetic cytochrome P450 2D6 polymorphism.

In this review we highlight the information available on the genetic polymorphism of cytochrome P4502D6 expression in man. An absent function of this enzyme is observed in 7-10 percent of the Caucasian population which are referred to as Poor metabolizers as opposed to the remainder of the population (Extensive Metabolizers). More than 30 widely used drugs have been identified as substrates for CYP2D6.

Immunohistochemical localization of cytochrome P450 2E1 in human pulmonary carcinoma and normal bronchial tissue.

Cytochrome P450 2E1 (CYP2E1) is a major xenobiotic-metabolizing enzyme but data concerning its extrahepatic expression are few. CYP2E1 can metabolically activate many procarcinogens and therefore its presence in the lung might play a role in bioactivation of procarcinogens, so we studied the expression and localization of CYP2E1 in primary pulmonary carcinomas and surrounding normal bronchial tissue from 28 patients. Seromucous glands showed expression of CYP2E1 in 19 and bronchial epithelium in 18 of the 28 samples of normal bronchial tissue.

Immunohistochemical localization of cytochrome P450 3A in human pulmonary carcinomas and normal bronchial tissue.

The cytochrome P450 (CYP) enzymes metabolize drugs and other xenobiotics in liver and also in some extrahepatic tissues. We have studied the expression and localization of CYP3A in primary lung tumours and normal lung tissue from the same patients. Thirty-two patients undergoing partial or total lung resection for therapy of primary pulmonary carcinoma were included in this study.

Influence of renal function on the steady-state pharmacokinetics of the antiarrhythmic propafenone and its phase I and phase II metabolites.

The aim of this study was to investigate the disposition of propafenone and its Phase I and II metabolites in relation to kidney function under steady-state conditions. The mechanism of the renal handling of propafenone glucuronides (filtration, secretion) was also examined. Racemic (R/S) propafenone was administered to 7 young volunteers, to 5 older patients with a normal glomerular filtration rate and to 4 patients with chronic renal failure.

Unpredictability of flecainide plasma concentrations in patients with renal failure: relationship to side effects and sudden death?

We report a retrospective evaluation of plasma concentrations of flecainide obtained from five dialysis patients during chronic oral treatment. A more than sevenfold variation in the dose/concentration relationship was observed. Plasma concentrations of flecainide above 1,200 ng/ml appeared to be associated with serious side effects and in one case with sudden death.

An enantiomer-enantiomer interaction of (S)- and (R)-propafenone modifies the effect of racemic drug therapy.

Background: Therapy with racemic compounds produces effects that can be attributed to both (S)- and (R)-enantiomers. Here we have tested the hypothesis that an enantiomer-enantiomer interaction would modulate the effects of treatment with a racemate, the antiarrhythmic propafenone. Previous studies have shown that while the enantiomers of propafenone exert similar sodium channel-blocking (QRS widening) effects, it is the (S)-enantiomer that produces beta-blockade; moreover, we have demonstrated recently that (R)-propafenone inhibits the metabolism of (S)-propafenone in vitro.

Variable disposition kinetics and electrocardiographic effects of flecainide during repeated dosing in humans: contribution of genetic factors, dose-dependent clearance, and interaction with amiodarone.

We studied the influence of cytochrome P450 2D6 (CYP2D6) on the steady-state disposition kinetics and the electrocardiographic effects of flecainide at two doses and during combination with amiodarone. Seven extensive and five poor metabolizers of dextromethorphan were studied during a three-period crossover study. All subjects received 50 mg flecainide every 12 hours, alone or together with 200 mg amiodarone every 12 hours, and 100 mg flecainide every 12 hours for 5 days.