Codeine phosphate in paediatric medicine
2001; Elsevier BV; Volume: 86; Issue: 3 Linguagem: Inglês
10.1093/bja/86.3.413
ISSN1471-6771
AutoresDavid G. Williams, D. J. Hatch, Richard F. Howard,
Tópico(s)Pain Mechanisms and Treatments
ResumoCodeine is an old drug that still enjoys widespread clinical use although the logical basis for its popularity has been questioned.66Lasagna L Clinical evaluation of morphine and its substitutes as analgesics.Pharmacol Rev. 1964; 16: 47-82PubMed Google Scholar It is considered to be suitable for mild to moderate pain but not for more intense pain even in large doses.94Reisime T Pasternak G Opioid analgesics and antagonists.in: Hardman JG Limbird LE Mounoff PB Ruddon RW Goodman Gilman A Goodman and Gilman's: The Pharmacological Basis of Therapeutics. 9th Edn. McGraw-Hill, New York1996: 521-555Google Scholar The World Health Organisation has devised a three-step analgesic ladder for the progressive treatment of increasing pain; on this codeine is considered a weak opioid and occupies a position on the second step (Fig. 1).113World Health Organisation. Cancer Pain Relief. 1986Google Scholar A significant degree of unpredictable, variable or poor response to treatment with codeine has been reported in many human and animal studies. Indeed, some single dose studies in adults, have shown no difference between codeine and placebo,54Hoing S Murray KA An appraisal of codeine as an analgesic: single-dose analysis.J Clin Pharmacol. 1984; 24: 96-102Crossref PubMed Scopus (35) Google Scholar 60Jochimsen PR Noyes R Appraisal of codeine as an analgesic in older patients.J Am Geriatr Soc. 1978; 26: 521-523Crossref PubMed Scopus (14) Google Scholar and a quantitative systemic review suggests that codeine 60 mg has a number needed to treat (NNT) of 18 which is very high when compared with 5.0 for paracetamol 600 mg and 3.1 for the combination.78Moore A Collins S Carroll D McQuay H Paracetamol with and without codeine in acute pain: a quantitative systematic review.Pain. 1997; 70: 193-201Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar Codeine is frequently recommended for paediatric use.2Royal College of Paediatrics and Child Health Prevention and Control of Pain in Children. 1st Edn. BMJ Publishing Group, London1997Google Scholar 37Dollery C Therapeutic Drugs. 2nd Edn. Churchill Livingstone, Edinburgh1999: C317-C320Google Scholar 100Schehter NL Berde CB Yaster M Pain in Infants, Children and Adolescents. 1st Edn. Williams & Wilkins, Baltimore1993Google Scholar A recent survey of paediatric anaesthetists in the UK showed that alongside morphine and fentanyl, codeine is the most widely prescribed opioid analgesic in paediatric anaesthetic practice.34de-Lima J Lloyd-Thomas AR Howard RF Sumner E Quinn TM Infant and Neonatal Pain: anaesthetists' perceptions and prescribing patterns.BMJ. 1996; 313: 787Crossref PubMed Scopus (85) Google Scholar The reputedly lower incidence of opioid-related side effects has made codeine popular for the younger age groups including neonates and especially in situations where airway management and neurological assessment are critical.56Husband AD Davis A Pain after tonsillectomy.Clin Otalaryngol. 1996; 21: 99-101Crossref PubMed Scopus (75) Google Scholar 69Lloyd-Thomas AR Pain management in paediatric patients.Br J Anaesth. 1990; 64: 85-104Crossref PubMed Scopus (133) Google Scholar 102Semple D Russell S Doyle E Aldridge LM Comparison of morphine sulphate and codeine phosphate in children undergoing adenotonsillectomy.Paediatr Anaesth. 1999; 9: 135-138Crossref PubMed Scopus (30) Google Scholar 106Stoneham MD Walters FJM Post-operative analgesia for craniotomy patients: current attitudes among neuroanaesthetists.Eur J Anaesthesiol. 1995; 12: 571-575PubMed Google Scholar These suggested benefits have been noted after single doses although they may not exist when repeated doses are used.69Lloyd-Thomas AR Pain management in paediatric patients.Br J Anaesth. 1990; 64: 85-104Crossref PubMed Scopus (133) Google Scholar In fact, few clinical studies of the analgesic efficacy or side effects of codeine in children have been undertaken, and although the incidence of side effects may be low, analgesia may be inadequate for post-operative pain in some circumstances.102Semple D Russell S Doyle E Aldridge LM Comparison of morphine sulphate and codeine phosphate in children undergoing adenotonsillectomy.Paediatr Anaesth. 1999; 9: 135-138Crossref PubMed Scopus (30) Google Scholar Pain assessment is difficult in paediatric populations especially neonates and preverbal children and this complicates both the study and use of analgesics particularly those with low efficacy or unpredictable effects. Significant variability in both the pharmacokinetics and pharmacodynamics of codeine has been shown in animal and adult human laboratory experimental studies.24Chen ZR Somogyi AA Reynolds G Bochner F Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.Br J Clin Pharmacol. 1991; 31: 381-390Crossref PubMed Scopus (132) Google Scholar 25Cleary J Mikus G Somogyi AA Bochner F The influence of pharmacogenetics on opioid analgesia: studies with codeine and oxycodone in the Sprague–Dawley/Dark Agouti rat model.J Pharmacol Exp Ther. 1994; 271: 1528-1534PubMed Google Scholar 38Eckhardt K Shuxia Li Ammon S Schanzle G Mikus G Eichelbaum M Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation.Pain. 1997; 76: 27-33Abstract Full Text Full Text PDF Scopus (226) Google Scholar 74Mikus G Somogyi AA Bochner F Eichelbaum M Codeine O-demethylation: rat strain differences and the effects of inhibitors.Biochem Pharmacol. 1991; 41: 757-762Crossref PubMed Scopus (45) Google Scholar 105Sindrup SH Brosen K Bjerring P et al.Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metaboliers of sparteine.Clin Pharmacol Ther. 1990; 48: 686-693Crossref PubMed Scopus (192) Google Scholar 112Wilder-Smith CH Hufschmid E Thormann W The visceral and somatic antinociceptive effects of dihydrocodeine and its metabolite, dihydromorphine. A cross-over study with extensive and quinidine-induced poor metabolisers.Br J Clin Pharmacol. 1998; 45: 575-581Crossref PubMed Scopus (48) Google Scholar 115Yue QY Hasselstrom J Svensson J-O Sawe J Pharmacokinetics of codeine and its metabolites in caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine.Br J Clin Pharmacol. 1991; 31: 635-642Crossref PubMed Scopus (121) Google Scholar In this review we shall examine the reasons for this variability and unpredictability in the effects of codeine in both laboratory and clinical investigations and assess evidence for its suitability for use in preverbal infants and children. Codeine (Fig. 2) is a naturally occurring opium alkaloid: 7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-morphinan- 6-ol monohydrate.1Reynolds JEF Martindale The Complete Drug Reference. 31st Edn. The Royal Pharmaceutical Society, Pharmaceutical Publications Department, UK1996: 29Google Scholar Like morphine it is a constituent of the opium poppy, Papaver somniferum. It was isolated from opium in 1833 by Robiquet and its pain-relieving effects were recognized shortly after. Codeine constitutes about 0.5% of opium, which continues to be a useful source of its production, although the bulk of codeine used medicinally is prepared by the methylation of morphine. Codeine is less potent than morphine, with a potency ratio of 1:10.111Wallenstein SL Houde RW Bellwille JW Relative potency and effectiveness of codeine and morphine.Fed Proc. 1961; 20: 311Google Scholar Codeine can be given by the oral, rectal and intramuscular (i.m.) routes. The intravenous (i.v.) route is not recommended because of dangerous hypotensive effects probably related to histamine release.85Parke TJ Nandi PR Bird KJ Jewkes DA Profound hypotension following intravenous codeine phosphate. Three case reports and some recommendations.Anaesthesia. 1992; 47: 852-854Crossref PubMed Scopus (23) Google Scholar In children, it is generally given in doses of 1 mg kg−1 up to a maximum of 3 mg kg−1day−1; however, larger doses have been used.3British National Formulary. 40th Edn. British Medical Association and Royal Pharmaceutical Society of Great Britain, September 2000: 211-212Google Scholar 102Semple D Russell S Doyle E Aldridge LM Comparison of morphine sulphate and codeine phosphate in children undergoing adenotonsillectomy.Paediatr Anaesth. 1999; 9: 135-138Crossref PubMed Scopus (30) Google Scholar Codeine is often used in combination with other drugs, for example aspirin, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) and diphenhydramine in the treatment of mild to moderate pain. In neonates and children it has been used in both acute and chronic painful conditions and particularly for post-operative and cancer pain.34de-Lima J Lloyd-Thomas AR Howard RF Sumner E Quinn TM Infant and Neonatal Pain: anaesthetists' perceptions and prescribing patterns.BMJ. 1996; 313: 787Crossref PubMed Scopus (85) Google Scholar 51Hatch DJ Sumner E Hellman J Neonatal anaesthesia – basic principles.in: The Surgical Neonate: Anaesthesia and Intensive Care. Edward Arnold, London1995: 120-147Google Scholar 55Houck CS Troshynski T Berde CB Treatment of pain in children.in: Wall PD Melzack R A Textbook of Pain. Churchill Livingstone, Edingburgh1994: 1419-1434Google Scholar 69Lloyd-Thomas AR Pain management in paediatric patients.Br J Anaesth. 1990; 64: 85-104Crossref PubMed Scopus (133) Google Scholar 100Schehter NL Berde CB Yaster M Pain in Infants, Children and Adolescents. 1st Edn. Williams & Wilkins, Baltimore1993Google Scholar Its antitussive and constipating properties also mean that it is used in many cough, cold and antidiarrhoeal remedies. The vast majority of pharmacokinetic data for codeine has been obtained from investigations in adults. Very little information is available from studies in children or infants and to our knowledge there is no published work in neonates. Codeine is rapidly, and well absorbed following oral administration, approximately 50% undergoing pre-systemic metabolism in the gut and liver. Peak plasma concentration occurs after approximately 1 h and the plasma half-life is 3–3.5 h. Absorption is faster after i.m. injection, the time to peak plasma concentration is about 0.5 h. The volume of distribution is 3.6 litre kg−1 and the clearance is 0.85 litre min−1.37Dollery C Therapeutic Drugs. 2nd Edn. Churchill Livingstone, Edinburgh1999: C317-C320Google Scholar Rectal codeine has been recently introduced into paediatric practice. A study in healthy adult volunteers showed no difference in codeine bioavailability following rectal or oral administration with a systemic availability of about 90%.77Moolenaar F Grosmeijer G Visser J Meijer DK Rectal versus oral absorption of codeine phosphate in man.Biochem Drug Dispos. 1983; 4: 195-199Crossref PubMed Scopus (20) Google Scholar In the post-operative period these values may be less predictable; in one study clearance varied 4-fold and systemic availability after oral dosage was between 12 and 84%.86Persson K Hammarulund-Udenaes M Mortimer O Rane A The postoperative pharmacokinetics of codeine.Eur J Clin Pharmacol. 1992; 42: 666Crossref Scopus (23) Google Scholar Available research findings imply that age specific differences in the pharmacokinetics of codeine may be significant. In a comparison of i.m. and rectal codeine in children aged 3 months to 12 yr for post-operative analgesia, peak plasma levels of codeine were achieved as expected between 30 and 60 min in both groups but rectal bioavailability was found to be lower.72McEwan A Andrews KA Sigston PE et al.A comparison of rectal and intramuscular codeine phosphate in children following neurosurgery.Paediatr Anaesth. 2000; 10: 189-193Crossref PubMed Scopus (35) Google Scholar In another study of rectal codeine for post-operative analgesia in infants and children aged between 6 months and 4 yr, the mean initial half-life was 2.6 h, but in the infants of the lowest body weight, the half life was over 2 h longer than this mean value.92Quiding H Olsson GL Boreus LO Bondesson U Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration.Br J Clin Pharmacol. 1992; 33: 45-49Crossref PubMed Scopus (35) Google Scholar In addition, plasma drug concentration data indicate that a rectal dose of codeine of 0.5 mg kg−1 in children can result in similar, or slightly greater, plasma concentrations of codeine and its metabolites than after 60 mg orally in adults.89Quiding H Andersen P Bondesson U Boreus LU Hynning P-A Plasma concentrations of codeine and its metabolite, morphine, after single and repeated oral administration.Eur J Clin Pharmacol. 1986; 30: 673-677Crossref PubMed Scopus (87) Google Scholar More information is clearly required, particularly for neonates and in the post-operative setting in order to understand fully the effects of development on codeine pharmacokinetics in clinical situations. Codeine is principally metabolized in the liver in one of three ways: glucuronidation at the 6-OH position, the principal route; N-demethylation to norcodeine (10–20%); and O-demethylation to morphine (5–15%). Between 5 and 15% of the drug is excreted unchanged in the urine (Fig. 3). Other minor metabolites, normorphine and hydrocodone, have also been identified.1Reynolds JEF Martindale The Complete Drug Reference. 31st Edn. The Royal Pharmaceutical Society, Pharmaceutical Publications Department, UK1996: 29Google Scholar In 1948, Sanfilippo first suggested that the analgesic effect of codeine was because of the proportion of the drug metabolized to morphine and this has lead to the belief that codeine is a prodrug, with morphine as its principal active metabolite and having little or no intrinsic analgesic activity of its own.99Sanfilippo G Contributo sperimentale all'ipotesi della smetilazione della codeina nell'organismo. (I) Influenza della dose sull'assuefazione alla codeina. (II) Assuefazione alla codeina ottenuta con somministazione prolungata di morfina.Boll Soc Ital Biol Sperimentale. 1948; 24: 723-726PubMed Google Scholar The efficacy of a prodrug is dependent on the amount of active metabolite formed. Variable expression of the enzymes involved in the biotransformation of drugs can lead to substantial differences in the production rate and plasma concentration of metabolites, and hence, the efficacy of a prodrug. It has been known for some time that genetic variability in drug metabolism is an important cause of inter-individual variations in drug efficacy and maturation of enzyme systems is another important factor for certain compounds. O-Demethylation of codeine to morphine is dependent on the cytochrome P450 enzyme, CYP2D6, which is known to show genetic polymorphism,23Chen ZR Somogyi AA Bochner F Polymorphic O-demethylation of codeine.Lancet. 1988; ii: 914-915Abstract Scopus (104) Google Scholar 32Dayer P Desmeules J Leemann T Striberni R Bioactivation of the narcotic drug codeine in human liver is mediated by the polymorphic monooxygenase debrisoquine 4-hydroxylation (cytochrome P-450 dbl/bufl).Biochem Biophys Res Commun. 1988; 152: 411-416Crossref PubMed Scopus (183) Google Scholar 116Yue QY Svensson J-O Alm C Sjoqvist F Sawe J Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation.Br J Clin Pharmacol. 1989; 28: 639-645Crossref PubMed Scopus (136) Google Scholar whereas the other metabolic pathways for codeine are not dependent on this enzyme. N-Demethylation for example is catalysed by CYP3A, another P450 enzyme.52Hedenmalm K Sundgren M Granberg K Spigset O Dahlqvist R Urinary excretion of codeine, ethylmorphine, and their metabolites: relation to the CYP2D6 activity.Ther Drug Monit. 1997; 19: 643-649Crossref PubMed Scopus (17) Google Scholar 114Yue QY Alm C Svensson J-O Sawe J Quantification of the O- and N-demethylated metabolites and the glucuronidated metabolites of codeine relative to the debrisoquine metabolic ratio in urine in ultrarapid, rapid and poor debrisoquine hydroxylators.Ther Drug Monit. 1997; 19: 539-542Crossref PubMed Scopus (39) Google Scholar A large number of different genetic variants are known to exist for CYP2D6, which leads to a wide spectrum of metabolic capabilities within study populations.31Daly AK Brockmoller J Broly F et al.Nomenclature for human CYP2D6 alleles.Pharmacogenetics. 1996; 6: 193-202Crossref PubMed Scopus (458) Google Scholar 71Marez D Legrand M Sabbagh N et al.Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution.Pharmacogenetics. 1997; 7: 193-202Crossref PubMed Scopus (369) Google Scholar When discussing these differences, individuals are normally classified as either poor metabolizers (PM) or extensive metabolizers (EM) depending on the activity of the enzyme, although this is known to be an oversimplification (see below).45Gaedigk A Blum M Gaedigk R Eichelbaum M Meyer UA Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolisers of the debrisoquine/sparteine polymorphism.Am J Hum Genet. 1991; 48: 943-950PubMed Google Scholar 53Heim M Meyer UA Genotyping of poor metabolisers of debrisoquine by allele specific PCR amplification.Lancet. 1990; 336: 529-532Abstract PubMed Scopus (520) Google Scholar 61Kagimoto M Heim M Kagimoto K Zeugin T Meyer UA Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolisers of debrisoquine.J Biol Chem. 1990; 265: 17209-17214PubMed Google Scholar 120Zanger UM Vilbois F Hardwick JP Meyer UA Absence of hepatic cytochrome P450bufl causes genetically deficient debrisoquine oxidation in man.Biochemistry. 1988; 27: 5447-5454Crossref PubMed Scopus (164) Google Scholar Poor metabolizers will produce little or no morphine from codeine whereas extensive metabolizers will produce significant amounts of morphine although the actual amount produced may show wide variation.42Findlay JWA Jones EC Butz RF Welch RM Plasma codeine and morphine concentrations after therapeutic oral doses of codeine-containing analgesics.Clin Pharmacol Ther. 1978; 24: 60-68Crossref PubMed Scopus (94) Google Scholar 95Rogers JF Findlay JWA Hull JH et al.Codeine disposition in smokers and nonsmokers.Clin Pharmacol Ther. 1982; 32: 227Crossref Scopus (50) Google Scholar 105Sindrup SH Brosen K Bjerring P et al.Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metaboliers of sparteine.Clin Pharmacol Ther. 1990; 48: 686-693Crossref PubMed Scopus (192) Google Scholar The metabolic differences between PMs and EMs are known to remain constant even after chronic codeine dosing.24Chen ZR Somogyi AA Reynolds G Bochner F Disposition and metabolism of codeine after single and chronic doses in one poor and seven extensive metabolisers.Br J Clin Pharmacol. 1991; 31: 381-390Crossref PubMed Scopus (132) Google Scholar 115Yue QY Hasselstrom J Svensson J-O Sawe J Pharmacokinetics of codeine and its metabolites in caucasian healthy volunteers: comparisons between extensive and poor hydroxylators of debrisoquine.Br J Clin Pharmacol. 1991; 31: 635-642Crossref PubMed Scopus (121) Google Scholar Despite the popularity of codeine in paediatric practice, the influence of development on the efficacy and side effects of codeine has not been well investigated. It has been suggested that infants and neonates have a reduced metabolic capacity for codeine.92Quiding H Olsson GL Boreus LO Bondesson U Infants and young children metabolise codeine to morphine. A study after single and repeated rectal administration.Br J Clin Pharmacol. 1992; 33: 45-49Crossref PubMed Scopus (35) Google Scholar CYP2D6 activity is absent or less than 1% of adult values in fetal liver microsomes. O-Demethylation of codeine to morphine does not occur in utero but activity of the enzyme is known to increase markedly immediately after birth regardless of gestational age. This increase in enzyme activity is maintained, although it may still be below 25% of adult values before 5 yr old. The efficiency of the enzyme to carry out the O-demethylation reaction also appears to be much lower in neonates than in adults. The glucuronidation pathway is also immature at birth and it has been shown that it continues to develop after the neonatal period. In contrast, N-demethylation has been found to be equivalent to that in adults at all pre- and post-natal ages.59Jacqz-Aigrain E Cresteil T Cytochrome P450-dependent metabolism of dextromethorphan: fetal and adult studies.Dev Pharmacol Ther. 1992; 18: 161-168PubMed Google Scholar 64Ladona MG Lindstrom B Thyr C Dun-Ren P Rane A Differential fetal development of the O- and N-demethylation of codeine and dextromethorphan in man.Br J Clin Pharmacol. 1991; 32: 295-302Crossref PubMed Scopus (79) Google Scholar 65Ladona MG Spalding DJ Persson K Lindstrom B Rane A Metabolic pathways of ethylmorphine, codeine and dextromethorphan in human fetal liver.Eur J Clin Pharmacol. 1989; 36: A148Google Scholar 73McRorie TI Lynn AM Nespeca MK Opheim KE Slattery JT The maturation of morphine clearance and metabolism.Am J Dis Child. 1992; 146: 972-976PubMed Google Scholar 108Treluyer J-M Jacqz-Aigrain E Alvarez F Cresteil T Expression of CYP2D6 in developing human liver.Eur J Biochem. 1991; 202: 583-588Crossref PubMed Scopus (182) Google Scholar Humans have approximately 60 unique P450 genes, although only half a dozen, including CYP2D6, are responsible for the metabolism of the vast majority of the 'over the counter' and prescribed drugs. CYP2D6 is usually considered to be a hepatic enzyme but it is probably present in other organs and tissues, and has been identified in rat and canine brain tissue.43Fonne-Pfister R Bargetzi MJ Meyer UA MPTP, the neurotoxin inducing Parkinson's disease, is a potent competitive inhibitor of human and rat cytochrome P450 isoenzymes (P450bufl,P450db1) catalysing debrisoquine 4-hydroxylation.Biochem Biophys Res Commun. 1987; 148: 1144-1150Crossref PubMed Scopus (144) Google Scholar 68Lee EJD Moochhala S Tissue distribution of bufuralol hydroxylase activity in Sprague-Dawley rats.Life Sci. 1989; 44: 827-830Crossref PubMed Scopus (6) Google Scholar 83Niznik HB Tyndale RF Sallee FR et al.The dopamine transporter and cytochrome P450IID1 (debrisoquine-4-hydroxylase) in brain: resolution and identification of two distinct [3H]GBR-12935 binding proteins.Arch Bichem Biophys. 1990; 276: 424-432Crossref PubMed Scopus (205) Google Scholar 110Tyndale RF Sunahara R Inaba T Neuronal cytochrome P450IID1 (debrisoquine/sparteine-type): Potent inhibition of activity by (–)-cocaine and nucleotide sequence identity to human hepatic P450 gene CYP2D6.Mol Pharmacol. 1991; 40: 63-68PubMed Google Scholar It has also been identified in human brain preparations.8Allard P Marcusson JO Ross SB [3H]GBR-12935 binding to cytochrome P450 in the human brain.J Neurochem. 1994; 62: 342-348Crossref PubMed Scopus (28) Google Scholar Unlike the majority of the other P450 genes CYP2D6 is not inducible, although there is growing evidence associating the enzyme with a number of disease states. Enhanced activity has been associated with malignancies of the bladder, liver, pharynx, stomach and, particularly, cigarette smoking related lung cancer. There has also been a link with chronic inflammatory diseases, such as rheumatoid arthritis and ankylosing spondylitis, and neurodegenerative disorders.17Caporaso N Pickle LW Bale S Ayesh R Heztel M Idle J The distribution of debrisoquine metabolic phenotypes and implications for the suggested association with lung cancer risk.Genet Epidemiol. 1989; 6: 517-524Crossref PubMed Scopus (30) Google Scholar 18Caporaso N Tucker MA Hoover RN et al.Lung cancer and the debrisoquine metabolic phenotype.J Natl Cancer Inst. 1990; 82: 1264-1272Crossref PubMed Scopus (173) Google Scholar 67Law MR Hetzel MR Idle JR Debrisoquine metabolism and genetic predisposition to lung cancer.Br J Cancer. 1989; 59: 686-687Crossref PubMed Scopus (72) Google Scholar 71Marez D Legrand M Sabbagh N et al.Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution.Pharmacogenetics. 1997; 7: 193-202Crossref PubMed Scopus (369) Google Scholar 96Roots I Drakoulis N Ploch M et al.Debrisoquine hydroxylation phenotype, acetylation phenotype, and ABO blood groups as genetic host factors of lung cancer risk.Klin Wochenschr. 1988; 66: 87-89Crossref PubMed Scopus (20) Google Scholar Enhanced CYP2D6 mediated metabolism of one or more dietary/environmental agents may form a reactive intermediate that plays a role in cancer initiation and/or promotion in various tissues.80Nebert DW Polymorphisms in drug-metabolising enzymes: what is their clinical relevance and why do they exist?.Am J Hum Genet. 1997; 60: 265-271PubMed Google Scholar Reduced enzyme activity is thought to be associated with an increased risk of Parkinson disease.5Parkinson Disease; PD. Online Mendelian Inheritance In Man.http://www3.ncbi.nlm.nhi.gov/entrez/dispomiumDate: 1999Google Scholar CYP2D6 polymorphism is responsible for variation in spartine/debrisoquine oxidation. This particular oxidative step is important in the metabolism of more than 30 drugs and environmental chemicals, including about 20% of commonly prescribed drugs, for example tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), some neuroleptics, some antiarrhythmics and β-adrenoreceptor blockers as well as codeine and tramadol.15Brosen K The pharmacogenetics of the selective serotonin reuptake inhibitors.Clin Invest. 1993; 71: 1002-1009Crossref PubMed Scopus (110) Google Scholar 16Brosen K Gram LF Clinical significance of the sparteine/debrisoquine oxidation polymorphism.Eur J Clin Pharmacol. 1989; 36: 537-547Crossref PubMed Scopus (311) Google Scholar The gene subfamily has been mapped to chromosome 22 at 22q13.1 and shows autosomal recessive inheritance. CYP2D6 activity ranges from complete deficiency to ultrafast metabolism, depending on which genetic variant is present.47Gough AC Smith CAD Howell SM Wolf CR Bryant SP Spurr NK Localization of the CYP2D gene locus to human chromosome 22q13.1 by polymerase chain reaction, in situ hybridization, and linkage analysis.Genomics. 1993; 15: 430-432Crossref PubMed Scopus (56) Google Scholar To date, 55 variants have been identified and classified.31Daly AK Brockmoller J Broly F et al.Nomenclature for human CYP2D6 alleles.Pharmacogenetics. 1996; 6: 193-202Crossref PubMed Scopus (458) Google Scholar 71Marez D Legrand M Sabbagh N et al.Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution.Pharmacogenetics. 1997; 7: 193-202Crossref PubMed Scopus (369) Google Scholar Most are rare with 87% of genotypes being accounted for by five different variants in the populations studied.71Marez D Legrand M Sabbagh N et al.Polymorphism of the cytochrome P450 CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution.Pharmacogenetics. 1997; 7: 193-202Crossref PubMed Scopus (369) Google Scholar 98Sachse C Brockmoller J Hilderbard M Muller K Roots I Correctness of prediction of the CYP2D6 phenotype by genotyping 47 intermediate and poor metabolisers of debrisoquine.Pharmacogenetics. 1998; 8: 181-185Crossref PubMed Scopus (63) Google Scholar Classification of individuals as PMs or EMs correlates with the genetic variant expressed and the presence of activity altering mutations in the gene.45Gaedigk A Blum M Gaedigk R Eichelbaum M Meyer UA Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolisers of the debrisoquine/sparteine polymorphism.Am J Hum Genet. 1991; 48: 943-950PubMed Google Scholar 53Heim M Meyer UA Genotyping of poor metabolisers of debrisoquine by allele specific PCR amplification.Lancet. 1990; 336: 529-532Abstract PubMed Scopus (520) Google Scholar 61Kagimoto M Heim M Kagimoto K Zeugin T Meyer UA Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolisers of debrisoquine.J Biol Chem. 1990; 265: 17209-17214PubMed Google Scholar 120Zanger UM Vilbois F Hardwick JP Meyer UA Absence of hepatic cytochrome P450bufl causes genetically deficient debrisoquine oxidation in man.Biochemistry. 1988; 27: 5447-5454Crossref PubMed Scopus (164) Google Scholar This is done by either phenotyping, using sparteine, debrisoquine or dextromethorphan as the probe drug, or by genotyping, using DNA extracted from leucocytes for a polymerase chain reaction (PCR) DNA test.39Eichelbaum M Spannbrucker N Steincke B Dengler HJ Defective N-oxidation of sparteine in man; a new pharmacogenetic defect.Eur J Clin Pharmacol. 1979; 16: 187Google Scholar 41Evans DA Mahgoub A Sloan TP Idle JR Smith RL A family and population study of the genetic polymorphism of debrisoquine oxidation in a white British population.J Med Genet. 1980; 17: 102-105Crossref PubMed Scopus (528) Google Scholar 101Schmid B Bircher J Preisig R Kupfer A Polymorphic dextromethorphan metabolism: cosegregation of oxidative O-demethylation with debrisoquine hydroxylation.Clin Pharmacol Ther. 1985; 38: 618-624Crossref PubMed Scopus (418) Google Scholar Misclassification can occur in the presence of drugs that are inhibitors of CYP2D6, for example quinidine, metoclopramide, some neuroleptics, some SSRIs and some antiarrhythmics.15Brosen K The pharmacogenetics of the selective serotonin reuptake inhibitors.Clin Invest. 1993; 71: 1002-1009Crossref PubMed Scopus (110) Google Scholar 16Brosen K Gram LF Clinical significance of the sparteine/debrisoquine oxidation polymorphism.Eur J Clin Pha
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