Zeruesenay Desta

Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6)

The use of pimozide is associated with prolongation of the QT interval and fatal ventricular arrhythmia. We recently reported 2 fatal cases in patients taking pimozide and clarithromycin and we have shown that clarithromycin inhibits CYP3A‐mediated metabolism of pimozide in vitro. In this study, we examined the effect of clarithromycin on pimozide pharmacokinetics and QT interval changes in a total of 12 healthy subjects (7 men and 5 women), documented as extensive metabolizers or poor metabolizers of CYP2D6.

Selection of drugs to treat gastro-oesophageal reflux disease: the role of drug interactions.

Gastro-oesophageal reflux disease is probably the most common acid-peptic disease in Western countries, and the successful treatment of mild to moderate disease with pharmacotherapy has become commonplace. A large number of effective drugs are now available, and so the decision-making process for physicians increasingly relies on considerations other than pure efficacy. Cost, adverse effects and drug interactions have therefore become important, particularly in the most vulnerable patients — children, the elderly and patients who are ill and are taking medications that may influence the efficacy of antireflux therapy.Important drug interactions with antacids include the prevention of the absorption of antibacterials such as tetracycline, azithromycin and quinolones. H2 antagonists, proton pump inhibitors and prokinetic agents undergo metabolism by the cytochrome P450 (CYP) system present in the liver and gastrointestinal tract. Cimetidine is an inhibitor of CYP3A and it may cause significant interactions with drugs of narrow therapeutic range and low bioavailability that are metabolised by these enzymes. The gastroparietal proton pump inhibitors lansoprazole, omeprazole and pantoprazole are all primarily metabolised by a genetically polymorphic enzyme, CYP2C19, that is absent from approximately 3% of Caucasians and 20% of Asians. These drugs may also interact with CYP3A, but to a lesser extent.Interactions with prokinetic agents carry the greatest potential for harm. Metoclopramide is a dopamine antagonist that may cause extrapyramidal effects when administered alone at high concentrations, or when coadministered with antipsychotic agents such as haloperidol or phenothiazines. Cisapride is clearly able to prolong the electrocardiographic QT interval and cause lethal ventricular arrhythmias when its metabolism is slowed by interaction with inhibitors of CYP3A, such as erythromycin, ketoconazole or itraconazole.

Stereoselective determination of cisapride, a prokinetic agent, in human plasma by chiral high-performance liquid chromatography with ultraviolet detection: application to pharmacokinetic study

We have developed a simple, sensitive, specific and reproducible stereoselective high-performance liquid chromatography technique for analytical separation of cisapride enantiomers and measurement of cisapride enantiomers in human plasma. A chiral analytical column (ChiralCel OJ) was used with a mobile phase consisting of ethanol-hexane-diethylamine (35:64.5:0.5, v/v/v). This assay method was linear over a range of concentrations (5-125 ng/ml) of each enantiomer. The limit of quantification was 5 ng/ml in human plasma for both cisapride enantiomers, while the limit of detection was 1 ng/ml. Intra- and inter-day C.V.s did not exceed 15% for all concentrations except at 12.5 ng/ml for EII (+)-cisapride, which was approximately 20 and 19%, respectively. The clinical utility of the method was demonstrated in a pharmacokinetic study of normal volunteers who received a 20 mg single oral dose of racemic cisapride. The preliminary pharmacokinetic data obtained using the method we describe here provide evidence for the first time that cisapride exhibits stereoselective disposition.

Sensitive assay for pimozide in human plasma using high-performance liquid chromatography with fluorescence detection: application to pharmacokinetic studies

A method is described for the measurement of pimozide in human plasma using HPLC with fluorescence detection. The method is specific and sensitive in the range of concentrations seen in human plasma after conventional dosing (1-15 ng/ml) with a limit of quantification of 1 ng/ml. The calibration curves are linear for concentrations between 1 and 50 ng/ml. Within-day and inter-day coefficients of variation are less than 7.4% and 15.5%, respectively, at three concentrations of pimozide (2, 10 and 20 ng/ml). Intra-day and inter-day bias are less than 18.5% and 12.5%, respectively. A pharmacokinetic study conducted in a healthy volunteer administered 6 mg of pimozide orally demonstrates the utility of this method.

Identification and characterization of human cytchrome P450 (CYP) isoforms interacting with cisapride

Clinical Pharmacology & Therapeutics (1999) 65, 126–126; doi:

Commentary on McIntyre IM, King CV, Staikos V, Gall J, Drummer OH. A Fatality Involving Moclobemide, Sertraline and Pimozide. J Forensic Sci 1997;42:951–53

Commentary on McIntyre IM, King CV, Staikos V, Gall J, Drummer OH. A fatality involving moclobemide, sertraline and pimozide. J Forensic Sci 1997;42:951–53

Chapter 21 – Pharmacogenetics of Drug Metabolism

Publisher Summary nIn this chapter, common genetic polymorphisms affecting pharmacokinetics via effects on drug metabolism are outlined and their clinical relevances are discussed. The goal of effective and safe therapy of many drugs is made difficult by large interpatient variability in response and toxicity, and this problem is a substantial burden for patients, their caretakers, and the healthcare system. For many drugs, the response to chronic administration is determined by the area under the plasma concentration time curve (AUC), during a dosing interval at steady state, a measure of drug exposure. An increasing number of drug metabolizing enzymes have been shown to result in large pharmacokinetic changes through a variety of different mechanisms. Drugs that are most affected are those that have a dominant route of clearance by a genetically polymorphic enzyme. The effects of such pharmacokinetic changes are most important in settings where clinically important pharmacodynamic change ensues. Pharmacogenetics tests that are most valuable are those for specific drugs for which the prediction of activity or adverse effects is important and difficult to anticipate given our current clinical tools and technologic capability. Although data from a variety of platforms documenting a wide range of genetic variability are being accumulated rapidly and clinical genetic tests have been recommended or implemented for drugs such as mercaptopurine, azathioprine, warfarin, irinotecan, and tamoxifen, there is still a great need for well-designed, prospective clinical trials that test pharmacogenetic approaches versus standard practice.

Cytochrome P450 3A4*22, PPAR-α, and ARNT polymorphisms and clopidogrel response

Recent candidate gene studies using a human liver bank and in vivo validation in healthy volunteers identified polymorphisms in cytochrome P450 (CYP) 3A4 gene (CYP3A4*22), Ah-receptor nuclear translocator (ARNT), and peroxisome proliferator-activated receptor-α (PPAR-α) genes that are associated with the CYP3A4 phenotype. We hypothesized that the variants identified in these genes may be associated with altered clopidogrel response, since generation of clopidogrel active metabolite is, partially mediated by CYP3A activity. Blood samples from 211 subjects, of mixed racial background, with established coronary artery disease, who had received clopidogrel, were analyzed. Platelet aggregation was determined using light transmittance aggregometry (LTA). Genotyping for CYP2C19*2, CYP3A4*22, PPAR-α (rs4253728, rs4823613), and ARNT (rs2134688) variant alleles was performed using Taqman® assays. CYP2C19*2 genotype was associated with increased on-treatment platelet aggregation (adenosine diphosphate 20 μM; P=0.025). No significant difference in on-treatment platelet aggregation, as measured by LTA during therapy with clopidogrel, was demonstrated among the different genotypes of CYP3A4*22, PPAR-α, and ARNT. These findings suggest that clopidogrel platelet inhibition is not influenced by the genetic variants that have previously been associated with reduced CYP3A4 activity.