Genetic polymorphism of CYP2D6

Indian Journal of Pharmacology 01/2001; 33:147-169.

ABSTRACT CYP2D6 is polymorphically distributed and is responsible for the metabolism of several clinically important drugs. It is also related to several pathophysiological conditions. Defect alleles, causing poor metaboliser (PM) phenotype and alleles with duplicated or multiduplicated active genes, causing ultra extensive metabolism (UEM) have been described. CYP2D6 polymorphism exhibits pronounced interethnic variation. While initial observation and studies focused on population of Caucasian origin, later other populations also studied extensively. Differences in metabolism of drugs can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of pharmacologically active drug or metabolite. Knowledge of individual's CYP2D6 status may be clinically and economically important and could provide the basis for a rational approach to drug prescription. Genetic polymorphism CYP2D6 pharmacogenetics KEY WORDS CYP 'CYP' is the abbreviation for cytochrome P-450, a subgroup of related enzymes or isoenzymes located in the endoplasmic reticulum and expressed mainly in the liver. It is also present in other organs, such as the intestine and the brain 4 . In mammals, most xenobiotics are metabolised via hepatic phase 1 metabolism by means of CYP monooxygenases 5 . Thirty or more different forms of these haem thiolate proteins have been characterized in humans 3 . The P450 superfamily is composed of families and sub-families of enzyme that are defined solely on the basis of their amino acid sequence similarities. With few exceptions, a P450 protein sequence from one fam-ily exhibits upto 40% resemblance to a P450 from other family. P450s with in a single subfamily always share greater than 55% sequence similarity 6,7 .

1 Bookmark
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Carbamazepine is a (CYP1A2 and CYP3A4 enzyme inducer) medicine which is used by epileptic patients for a long time. During the course of therapy, patients are generally caught by other diseases like urinary tract infections, upper respiratory tract infection, skin and soft tissue infection etc. To cure them, physicians commonly prescribe fluoroquinolones like Ciprofloxacin (CYP1A2 inhibitor) along with Carbamazepine (CBZ). Interactions may result without recognition which may lead to unforeseen toxicity, untoward effects or even therapeutic failure. Therefore, studies were conducted to investigate the effect of Ciprofloxacin on the pharmacokinetics of carbamazepine in healthy adult male volunteers. The main objective of this study was to generate new knowledge regarding CBZ and ciprofloxacin interaction for physicians and research workers dealing with these medicines. Eight healthy adult male volunteers were selected to assess the effect of ciprofloxacin on the pharmacokinetics of carbamazepine. After overnight fast the selected male volunteers were given CBZ orally. Blood samples were drawn at different time intervals after medication. Then the same volunteers were given CBZ along with ciprofloxacin. Blood samples were again drawn at the same time intervals as done previously. Plasma was separated from the blood samples. Concentration of CBZ in the plasma samples was determined by using HPLC technique. Results of the present study indicated that ciprofloxacin significantly increased the plasma concentration of CBZ when given concurrently to the healthy adult male volunteers. Ciprofloxacin increased Cmax, AUC and t½ while it decreased the CL and Vd of CBZ when administered concurrently to the adult volunteers. Change in pharmacokinetic parameters was due to slow metabolism or elimination of CBZ when given concurrently with ciprofloxacin to the adult volunteers. This is probably due to the inhibition of CYP3A4 isoenzyme by ciprofloxacin which is responsible for metabolism of CBZ. Ciprofloxacin increased the plasma concentration of CBZ so dose adjustment as well as drug monitoring of CBZ is required when both the drugs are given concurrently. The knowledge regarding interaction between ciprofloxacin and CBZ would be helpful for the pharmaceutical industries, physicians and a blessing for the patients.
    Pakistan journal of pharmaceutical sciences 01/2011; 24(1):63-8. · 0.95 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetically determined individual differences in the ability to oxidize certain drugs have raised recently a considerable interest because of clinical importance of this problem. Determination of CYP2D6 oxidation phenotype is used to obtain more efficient pharmacotherapy and to explain lower efficacy of some drugs and presentation of adverse effects in particular patients. The aim of this study was to identify the CYP2D6 oxidation phenotype with dextromethorphan (DM) as a probe drug. The study included 85 healthy volunteers of Polish origin. DM (40 mg) was given orally to healthy adults and 10-h urine samples were collected. DM and the metabolite dextrorphan (DX) were analyzed by the HPLC method. Phenotyping was performed using the metabolic ratio (MR) calculated as the urinary DM/DX output. Based on the metabolic ratio, we can distinguish extensive (EM) and poor (PM) metabolizers in human population. Individuals with a dextromethorphan MR greater than 0.3 (log > -0.5) were classified as PMs. In our study, the frequency of the PM phenotype was 9.4%, which is in the range found in other Caucasian populations (3-10%).
    Pharmacological reports: PR 11/2007; 59(6):734-8. · 1.97 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The present study aimed as a first attempt on the North Indian population to establish the CYP2C19 phenotype frequencies among the population of Uttarakhand. A total of 20 physically healthy and unrelated human subjects of either sex (both male and female), with age range from 18-30 yrs, body weight ≥ 40 kg, participated in this study. After an overnight fast, each subject received a single dose of 20 mg omeprazole capsule orally. Blood samples (5ml) were collected just before (at 0 hr) and 3 hr after the drug administration. Plasma was separated after centrifugation and stored at -20ºC until analysis. The plasma concentrations of omeprazole and its metabolite, 5-hydroxyomeprazole, were determined by using High performance liquid chromatography (HPLC) method of analysis with some modifications. The metabolites were separated using a mixture of acetonitrile: 0.05 M phosphate buffer (20:80, ph 8.5) at flow rate of 1.5 ml/min. Metabolites were detected by their absorbance at 250 nm. Amounts were calculated from standard curves of omeprazole and its metabolite constructed in the concentration range of 10–1000 ng/ml. Out of 20 subjects, 17 (85%) were EMs and 03 (15%) were PMs. The prevalence of PMs in study population of Uttarakhand was found to be 15% by phenotyping, which is slightly greater than frequencies of South Indians (14%), Gujratis and Marwadis (10.32%), Southeast Asians like Thai (9.2%), Burmese (11%) and Karen (8.4%), Koreans (12.6%) and some other North Indians (10-12%). On the other hand, this PM frequency of 15% is found to be lower than the frequency found in Mexicans (31%), Japanese (27-35%). Our study population possesses 15% PMs, which is essential to evaluate the phenotype-genotypes correlation in this population after the genotyping data is available. It is now further suggested that future studies on genetic polymorphism on subjects of Uttarakhand be carried out on large study population for better interpretation and may involve the correlation of phenotype-genotype data along with observations that relate them to the findings such as adverse drug reaction monitoring, drug therapy decisions like cost and duration of therapy.
    International Journal of Advances in Pharmaceutical Sciences. 01/2010; 1:358-363.

Full-text (2 Sources)

Available from
May 19, 2014