FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2022972328> ?p ?o ?g. }

• W2022972328 endingPage "306" @default.
• W2022972328 startingPage "293" @default.
• W2022972328 abstract "Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ([email protected]). Therapeutic Reviews aim to provide essential independent information for health professionals about drugs used in palliative and hospice care. Additional content is available on www.palliativedrugs.com. Country-specific books (Hospice and Palliative Care Formulary USA, and Palliative Care Formulary, British and Canadian editions) are also available and can be ordered from www.palliativedrugs.com. The series editors welcome feedback on the articles ([email protected]). Adenosine triphosphate Central nervous system Extensive (rapid) metabolizer Food and Drug Administration Gastrointestinal Human immunodeficiency virus International normalized ratio Nonsteroidal anti-inflammatory drug Package insert Poor (slow) metabolizer Per os, by mouth Proton-pump inhibitor Selective serotinin re-uptake inhibitor Tricyclic antidepressant Uridine diphosphate UDP-glycosyltransferase Ultra-rapid metabolizer Urinary tract infection There is great inter-individual variability in the way people respond to a drug (Box A). Some of this variability is predictable in the presence of clinical factors known to impact upon the pharmacokinetics and/or pharmacodynamics of a drug. For example, an age-related decrease in overall metabolic capacity of the liver, because of reductions in liver mass, liver enzyme activity and hepatic blood flow, results in the elderly being at a significantly higher risk of toxicity from drugs metabolized in the liver. Similarly, an age-related decline in renal function can reduce the excretion of active drugs and metabolites, e.g., morphine-6-glucuronide and morphine-3-glucuronide, increasing the risk of toxicity from morphine.Box ACommon factors affecting response to drugsAdherenceWhether drug regimen adhered to or notGenetic variation/polymorphismSequence variation including single nucleotide polymorphisms, gene deletions, gene duplications resulting in altered protein function, e.g., receptors, enzymes, drug transportersPharmacokineticsAbsorptionDistributionMetabolismDrug–drug and drug–food interactionsExcretionPharmacodynamicsReceptor–drug interaction and effectDrug–drug and drug–food interactionsDecreased/increased receptor affinity due to concurrent disease statePhysiological factorsGenderAgeEthnicityHormonal changesCircadian and seasonal factorsEnvironmental factorsDietEnvironmental toxinsAlcohol and recreational drugsSmokingPotential specific associations/concomitant diseaseDiabetes mellitusGI microbiologyHypoalbuminemiaLiver failureMalabsorptionMalnutritionObesityRenal failure AdherenceWhether drug regimen adhered to or notGenetic variation/polymorphismSequence variation including single nucleotide polymorphisms, gene deletions, gene duplications resulting in altered protein function, e.g., receptors, enzymes, drug transportersPharmacokineticsAbsorptionDistributionMetabolismDrug–drug and drug–food interactionsExcretionPharmacodynamicsReceptor–drug interaction and effectDrug–drug and drug–food interactionsDecreased/increased receptor affinity due to concurrent disease statePhysiological factorsGenderAgeEthnicityHormonal changesCircadian and seasonal factorsEnvironmental factorsDietEnvironmental toxinsAlcohol and recreational drugsSmokingPotential specific associations/concomitant diseaseDiabetes mellitusGI microbiologyHypoalbuminemiaLiver failureMalabsorptionMalnutritionObesityRenal failure Genetic variations also contribute towards differences in drug response. Clinically, these are less predictable, although some may be detected with specific testing. They are particularly important for drugs metabolized by cytochrome P450 (CYP450) with the rate of metabolism either reduced or increased. Examples of how these manifest include:•reduced or no response because of➢the failure to convert a pro-drug to its active form➢increased metabolism of an active drug to an inactive metabolite•increased toxicity because of➢more rapid conversion to the active form or to a metabolite which is more active than the parent drug➢failure to metabolize an active drug to inactive metabolite(s). Other genetic variations, such as genes coding for receptors or drug transporters also can influence overall response, e.g., the μ-opioid receptor or P-glycoprotein transporter and the response to opioids. Induction or inhibition of CYP450 activity also can result from a drug–drug or drug–food interaction causing similar manifestations to those resulting from genetic variation. Each of these factors is considered in more detail below. Many factors contribute to the inter-individual variation in response to opioids.1Droney J. Riley J. Ross J.R. Evolving knowledge of opioid genetics in cancer pain.Clin Oncol (R Coll Radiol). 2011; 23: 418-428Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 2Branford R. Droney J. Ross J.R. Opioid genetics: the key to personalized pain control?.Clin Genet. 2012; 82: 301-310Crossref PubMed Scopus (49) Google Scholar, 3Ross J.R. Riley J. Quigley C. Welsh K.I. Clinical pharmacology and pharmacotherapy of opioid switching in cancer patients.Oncologist. 2006; 11: 765-773Crossref PubMed Scopus (44) Google Scholar, 4Somogyi A.A. Barratt D.T. Coller J.K. Pharmacogenetics of opioids.Clin Pharmacol Ther. 2007; 81: 429-444Crossref PubMed Scopus (278) Google Scholar This is the key receptor mediating opioid analgesia.5Matthes H. Maldonado R. Simonin F. et al.Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene.Nature. 1996; 383: 819-823Crossref PubMed Scopus (1407) Google Scholar Genetic variation in the μ-opioid receptor gene has been associated with variation in opioid response in acute post-operative pain,6Chou W.Y. Yang L.C. Lu H.F. et al.Association of mu-opioid receptor gene polymorphism (A118G) with variations in morphine consumption for analgesia after total knee arthroplasty.Acta Anaesthesiol Scand. 2006; 50: 787-792Crossref PubMed Scopus (241) Google Scholar, 7Chou W.Y. Wang C.H. Liu P.H. et al.Human opioid receptor A118G polymorphism affects intravenous patient-controlled analgesia morphine consumption after total abdominal hysterectomy.Anesthesiology. 2006; 105: 334-337Crossref PubMed Scopus (251) Google Scholar, 8Sia A.T. Lim Y. Lim E.C. et al.A118G single nucleotide polymorphism of human mu-opioid receptor gene influences pain perception and patient-controlled intravenous morphine consumption after intrathecal morphine for postcesarean analgesia.Anesthesiology. 2008; 109: 520-526Crossref PubMed Scopus (248) Google Scholar chronic non-cancer pain,9Janicki P.K. Schuler G. Francis D. et al.A genetic association study of the functional A118G polymorphism of the human mu-opioid receptor gene in patients with acute and chronic pain.Anesth Analg. 2006; 103: 1011-1017Crossref PubMed Scopus (136) Google Scholar, 10Lotsch J. von Hentig N. Freynhagen R. et al.Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers.Pharmacogenet Genomics. 2009; 19: 429-436Crossref PubMed Scopus (93) Google Scholar and cancer pain.11Campa D. Gioia A. Tomei A. Poli P. Barale R. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief.Clin Pharmacol Ther. 2008; 83: 559-566Crossref PubMed Scopus (279) Google Scholar, 12Klepstad P. Rakvåg T.T. Kaasa S. et al.The 118 A > G polymorphism in the human mu-opioid receptor gene may increase morphine requirements in patients with pain caused by malignant disease.Acta Anaesthesiol Scand. 2004; 48: 1232-1239Crossref PubMed Scopus (339) Google Scholar However, meta-analysis of opioid pain studies showed no overall association with pain and only weak associations with morphine dose or undesirable effects.13Walter C. Lotsch J. Meta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment.Pain. 2009; 146: 270-275Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar The membrane-bound drug transporter P-glycoprotein influences drug absorption and drug excretion.14Schinkel A.H. The physiological function of drug-transporting P-glycoproteins.Semin Cancer Biol. 1997; 8: 161-170Crossref PubMed Scopus (440) Google Scholar, 15Marzolini C. Paus E. Buclin T. Kim R.B. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance.Clin Pharmacol Ther. 2004; 75: 13-33Crossref PubMed Scopus (826) Google Scholar It limits the uptake of compounds from the GI tract, regulates the transfer of various drugs across the blood–brain barrier,16Ross J.R. Quigley C. Pharmacogenetics and opioids.in: Davis M.P. Glare P.A. Hardy J. Quigley C. Opioids in cancer pain. 2nd ed. Oxford University Press, Oxford2009: 287-299Crossref Google Scholar and influences drug excretion by the liver and kidneys. It is encoded by the ATP-binding cassette subfamily B member 1 (ABCB1) gene. P-glycoprotein modulation of opioid CNS concentrations varies substantially between opioids, with morphine, fentanyl, and methadone being among those most affected.17Dagenais C. Graff C.L. Pollack G.M. Variable modulation of opioid brain uptake by P-glycoprotein in mice.Biochem Pharmacol. 2004; 67: 269-276Crossref PubMed Scopus (196) Google Scholar, 18Barratt D.T. Coller J.K. Hallinan R. et al.ABCB1 haplotype and OPRM1 118A > G genotype interaction in methadone maintenance treatment pharmacogenetics.Pharmgenomics Pers Med. 2012; 5: 53-62PubMed Google Scholar In animals, removal of P-glycoprotein activity (“knockout” mice) or inhibition by cyclosporine enhances absorption and increases CNS concentrations of fentanyl and morphine, resulting in prolonged analgesia.19Thompson S.J. Koszdin K. Bernards C.M. Opiate-induced analgesia is increased and prolonged in mice lacking P-glycoprotein.Anesthesiology. 2000; 92: 1392-1399Crossref PubMed Scopus (247) Google Scholar Thus, inhibitors of P-glycoprotein (e.g., clarithromycin, cyclosporine, erythromycin, itraconazole, ketoconazole [not UK], quinidine [not UK], verapamil) could increase CNS effects of opioids. Variation in ABCB1 has been associated with increased pain relief with morphine in cancer pain11Campa D. Gioia A. Tomei A. Poli P. Barale R. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief.Clin Pharmacol Ther. 2008; 83: 559-566Crossref PubMed Scopus (279) Google Scholar and decreased opioid requirements in mixed chronic pain.10Lotsch J. von Hentig N. Freynhagen R. et al.Cross-sectional analysis of the influence of currently known pharmacogenetic modulators on opioid therapy in outpatient pain centers.Pharmacogenet Genomics. 2009; 19: 429-436Crossref PubMed Scopus (93) Google Scholar Studies have shown conflicting results in relation to opioid-induced nausea and vomiting and other undesirable effects.20Ross J.R. Riley J. Taegetmeyer A.B. et al.Genetic variation and response to morphine in cancer patients: catechol-O-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects.Cancer. 2008; 112: 1390-1403Crossref PubMed Scopus (107) Google Scholar, 21Zwisler S.T. Enggaard T.P. Noehr-Jensen L. et al.The antinociceptive effect and adverse drug reactions of oxycodone in human experimental pain in relation to genetic variations in the OPRM1 and ABCB1 genes.Fundam Clin Pharmacol. 2010; 24: 517-524Crossref PubMed Scopus (83) Google Scholar, 22Coulbault L. Beaussier M. Verstuyft C. et al.Environmental and genetic factors associated with morphine response in the postoperative period.Clin Pharmacol Ther. 2006; 79: 316-324Crossref PubMed Scopus (207) Google Scholar Catechol-O-methyltransferase (COMT) is an enzyme that has a significant impact on the metabolism of several important neurotransmitters: dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). The COMT gene is polymorphic, and <25% of Caucasians have low activity variants. One common variant in which the amino acid valine is substituted for methionine results in a 3–4 times decrease in COMT activity. It has been associated with increased pain sensitivity and higher μ-opioid system activation in experimental pain,23Kim H. Lee H. Rowan J. Brahim J. Dionne R.A. Genetic polymorphisms in monoamine neurotransmitter systems show only weak association with acute post-surgical pain in humans.Mol Pain. 2006; 2: 24Crossref PubMed Scopus (98) Google Scholar, 24Zubieta J.K. Heitzeg M.M. Smith Y.R. et al.COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor.Science. 2003; 299: 1240-1243Crossref PubMed Scopus (973) Google Scholar and increased morphine dose requirements in cancer patients.25Rakvag T.T. Klepstad P. Baar C. et al.The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene may influence morphine requirements in cancer pain patients.Pain. 2005; 116: 73-78Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar Other variants of the COMT gene are associated with increased undesirable opioid effects, e.g., nausea and vomiting.20Ross J.R. Riley J. Taegetmeyer A.B. et al.Genetic variation and response to morphine in cancer patients: catechol-O-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects.Cancer. 2008; 112: 1390-1403Crossref PubMed Scopus (107) Google Scholar, 26Laugsand E.A. Fladvad T. Skorpen F. et al.Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids.Eur J Cancer. 2011; 47: 1682-1691Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 27Kolesnikov Y. Gabovits B. Levin A. Voiko E. Veske A. Combined catechol-O-methyltransferase and mu-opioid receptor gene polymorphisms affect morphine postoperative analgesia and central side effects.Anesth Analg. 2011; 112: 448-453Crossref PubMed Scopus (102) Google Scholar Opioid metabolism takes place primarily in the liver. Opioids are metabolized via two main pathways, cytochrome P450 (CYP450) and UDP-glycosyltransferase (UGT; Table 1). Two phases of metabolism are generally described: phase 1 metabolism (modification reactions) and phase 2 metabolism (conjugation reactions).Table 1Major opioid enzyme pathwaysDrugPathwaya++ for CYP pathways may result in clinically important drug–drug interactions (see Appendix).CYP2D6CYP3A4/5CYP2B6UGTAlfentanil++Buprenorphine+++Codeine+++Dihydrocodeine++Fentanyl++Hydrocodone+Hydromorphone++Methadone+++Morphine++Oxycodone+++Oxymorphone++Sufentanil++Tapentadol++Tramadol++++a ++ for CYP pathways may result in clinically important drug–drug interactions (see Appendix). Open table in a new tab The most important phase 1 reaction is oxidation, catalyzed by CYP450. The most important phase 2 reaction is glucuronidation, catalyzed by UGT. Glucuronidation produces molecules that are highly hydrophilic and thus easily excreted by the kidneys.28Smith H.S. Opioid metabolism.Mayo Clin Proc. 2009; 84: 613-624Abstract Full Text Full Text PDF PubMed Scopus (495) Google Scholar Drug–drug interactions can occur as a result of changes in CYP450 or UGT activity, although the latter is less well documented.29Baxter K. Preston C.L. Stockley's drug interactions. Pharmaceutical Press, London2013www.medicinescomplete.comGoogle Scholar About 75% of all drugs are metabolized partly or completely by cytochrome P450 (Box B). Thus, variation in activity of the cytochrome P450 system can have a major impact on drug action.Box BCytochrome P450 (CYP450)30Wilkinson G.R. Drug metabolism and variability among patients in drug response.N Engl J Med. 2005; 352: 2211-2221Crossref PubMed Scopus (911) Google Scholar, 31Ingelman-Sundberg M. Daly A.K. Nebert D.W. Human Cytochrome P450 (CYP). Allele Nomenclature Committee, 2005www.CYPalleles.ki.seGoogle ScholarCYP450 is a super-family of numerous enzymic proteins responsible for the oxidative metabolism of many drugs and some endogenous substances (e.g., fatty acids, eicosanoids, steroids, bile acids).The root symbol used in naming the individual enzymes is CYP, followed by:•a number designating the enzyme family (18 in humans)•a capital letter designating the subfamily (44 in humans)•a number designating the individual enzyme.CYP450 enzymes exist in virtually all tissues, but their highest concentration is in the liver.The enzymes concerned with drug metabolism are mostly CYP1–CYP3; these account for about 70% of the total CYP450 content of the liver.The most important enzyme is CYP3A4, followed by CYP2D6 and CYP2C9The presence of CYP3A4 in the wall of the GI tract is important; it probably acts in conjunction with P-glycoprotein, and together determine the extent of the intestinal absorption and metabolism of CYP3A4 substrates. CYP450 is a super-family of numerous enzymic proteins responsible for the oxidative metabolism of many drugs and some endogenous substances (e.g., fatty acids, eicosanoids, steroids, bile acids).The root symbol used in naming the individual enzymes is CYP, followed by:•a number designating the enzyme family (18 in humans)•a capital letter designating the subfamily (44 in humans)•a number designating the individual enzyme. CYP450 enzymes exist in virtually all tissues, but their highest concentration is in the liver. The enzymes concerned with drug metabolism are mostly CYP1–CYP3; these account for about 70% of the total CYP450 content of the liver. The most important enzyme is CYP3A4, followed by CYP2D6 and CYP2C9 The presence of CYP3A4 in the wall of the GI tract is important; it probably acts in conjunction with P-glycoprotein, and together determine the extent of the intestinal absorption and metabolism of CYP3A4 substrates. Some 20–25% of drugs are affected by genetic variants of drug-metabolizing enzymes.32Stamer U.M. Zhang L. Stüber F. Personalized therapy in pain management: where do we stand?.Pharmacogenomics. 2010; 11: 843-864Crossref PubMed Scopus (60) Google Scholar The bulk of the population will manifest a normal distribution in terms of the rate of drug metabolism, with activity ranging from well below-average to well above-average, but generally lumped together as extensive metabolizers (EM).33Meyer U. Genotype or phenotype: the definition of a pharmacogenetic polymorphism.Pharmacogenetics. 1991; 1: 66-67Crossref PubMed Scopus (58) Google Scholar In addition, there are discrete genetic populations of individuals who fall beyond the ends of the spectrum. These are designated poor (PM) and ultra-rapid metabolizers (URM). More recently, intermediate metabolizers have been identified for some enzymes (Table 2).30Wilkinson G.R. Drug metabolism and variability among patients in drug response.N Engl J Med. 2005; 352: 2211-2221Crossref PubMed Scopus (911) Google ScholarTable 2Metabolizer status34Sajantila A. Palo J.U. Ojanperä I. Davis C. Budowle B. Pharmacogenetics in medico-legal context.Forensic Sci Int. 2010; 203: 44-52Abstract Full Text Full Text PDF PubMed Scopus (26) Google ScholarCategoryDescriptionPossible impactPoor (PM) or slowLacks functional enzyme (deletion of gene or non-functional variant)Increased toxicity due to slower drug metabolism (e.g., phenytoin, flecainide) orTherapeutic failure due to poor metabolism of a pro-drug to its active form (e.g., codeine) or a parent drug to an active metabolite (e.g., tramadol, tamoxifen)IntermediateHas two decreased-function enzymes or one decreased, one non-functionalComparable to slow metabolizer but less markedExtensive (EM) or rapidHas at least one fully-functional enzymeThis is the normUltra-rapid (URM)Increased enzyme activity (duplication of gene or other mutation); relatively rareTherapeutic failure due to faster drug metabolism orIncreased toxicity due to faster conversion of parent drug to more active metabolite (e.g., tramadol) or pro-drug to active form (e.g., codeine) Open table in a new tab As a general rule, an URM may need a higher dose to obtain a therapeutic effect, and a PM a lower dose to prevent increased undesirable effects (Table 3).32Stamer U.M. Zhang L. Stüber F. Personalized therapy in pain management: where do we stand?.Pharmacogenomics. 2010; 11: 843-864Crossref PubMed Scopus (60) Google Scholar Exceptions are ‘pro-drugs’ where metabolites are mostly responsible for the effect of the drug (see below). The effects of such genetic variations can be further modified by the co-administration of the relevant CYP450 inhibitor or inducer.Table 3Genetic polymorphism and PM/URM statusaThere is roughly a similar number of URM as PM.28Smith H.S. Opioid metabolism.Mayo Clin Proc. 2009; 84: 613-624Abstract Full Text Full Text PDF PubMed Scopus (495) Google Scholar, 30Wilkinson G.R. Drug metabolism and variability among patients in drug response.N Engl J Med. 2005; 352: 2211-2221Crossref PubMed Scopus (911) Google Scholar, 35Poulsen L. Arendt-Nielsen L. Brøsen K. Sindrup S.H. The hypoalgesic effect of tramadol in relation to CYP2D6.Clin Pharmacol Ther. 1996; 60: 636-644Crossref PubMed Scopus (366) Google Scholar, 36Riddick D. Drug biotransformation.in: Kalant H. Roschlau W. Principles of medical pharmacology. 6th ed. Oxford University Press, New York1997: 38-54Google Scholar, 37Williams D.G. Patel A. Howard R.F. Pharmacogenetics of codeine metabolism in an urban population of children and its implications for analgesic reliability.Br J Anaesth. 2002; 89: 839-845Crossref PubMed Scopus (209) Google ScholarPathwayA selection of affected drugsPopulation affectedCYP2C9NSAIDsCaucasians 35%PhenytoinAsian/African <1%Sulfonylureas (glipizide, tolbutamide)WarfarinCYP2C19Antidepressants (imipramine, sertraline)Asians 10–35%ClopidogrelbEnzyme conversion produces the main active or a more active metabolite.Africans 15%DiazepamCaucasians 2–5%PPIsCYP2D6β-Blockers (metoprolol)c70% Dose reduction recommended in PM; note also that co-administration with paroxetine (2D6 inhibitor) increases plasma concentrations four times.Africans 0–34%(debrisoquine hydroxylase)CodeinebEnzyme conversion produces the main active or a more active metabolite.Caucasians 5–10%FlecainideAsians ≤1%OxycodoneSSRIs (some, e.g., paroxetine)TamoxifenbEnzyme conversion produces the main active or a more active metabolite.TCAs (imipramine, nortriptyline)dTCAs most likely to need a lower dose.TramadolbEnzyme conversion produces the main active or a more active metabolite.a There is roughly a similar number of URM as PM.b Enzyme conversion produces the main active or a more active metabolite.c 70% Dose reduction recommended in PM; note also that co-administration with paroxetine (2D6 inhibitor) increases plasma concentrations four times.d TCAs most likely to need a lower dose. Open table in a new tab Of particular note is codeine, for which most of its analgesic effect results from partial conversion to morphine by O-demethylation catalyzed by CYP2D6.38Persson K. Hammarlund-Udenaes M. Mortimer O. Rane A. The postoperative pharmacokinetics of codeine.Eur J Clin Pharmacol. 1992; 42: 663-666Crossref PubMed Scopus (23) Google Scholar, 39Findlay J.W.A. Jones E.C. Butz R.F. Welch R.M. 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 Compared with the general population (EM), a PM produces little or no morphine from codeine, and obtains little or no pain relief. On the other hand, undesirable effects are comparable in both categories.40Eckhardt K. Li S. Ammon S. et al.Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation.Pain. 1998; 76: 27-33Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar, 41Susce M.T. Murray-Carmichael E. de Leon J. Response to hydrocodone, codeine and oxycodone in a CYP2D6 poor metabolizer.Prog Neuropsychopharmacol Biol Psychiatry. 2006; 30: 1356-1358Crossref PubMed Scopus (87) Google Scholar At the other extreme, URM produce more morphine; this can lead to life-threatening opioid toxicity, which, rarely, has been fatal in children (following adenoidectomy/tonsillectomy; altered respiratory drive due to obstructive sleep apnea was a probable contributing factor).42Gasche Y. Daali Y. Fathi M. et al.Codeine intoxication associated with ultrarapid CYP2D6 metabolism.N Engl J Med. 2004; 351: 2827-2831Crossref PubMed Scopus (585) Google Scholar, 43Koren G. Cairns J. Chitayat D. Gaedigk A. Leeder S.J. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother.Lancet. 2006; 368: 704Abstract Full Text Full Text PDF PubMed Scopus (533) Google Scholar, 44Kirchheiner J. Schmidt H. Tzvetkov M. et al.Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication.Pharmacogenomics J. 2007; 7: 257-265Crossref PubMed Scopus (349) Google Scholar, 45Racoosin J.A. Roberson D.W. Pacanowski M.A. Nielsen D.R. New evidence about an old drug - risk with codeine after adenotonsillectomy.N Engl J Med. 2013; 368: 2155-2157Crossref PubMed Scopus (72) Google Scholar, 46MHRA Codeine: restricted use as an analgesic in children and adolescents after European safety review.Drug Safety Update. 2013; 6 (Available at:) (Accessed October 14, 2014): S1http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON287006Google Scholar Genetic variation involving CYP2D6 is also important in relation to tramadol, for which the (+) O-desmethyltramadol metabolite is responsible for the opioid analgesic effect. A PM produces little or none and thus obtains little or no analgesic benefit;47Stamer U.M. Musshoff F. Kobilay M. et al.Concentrations of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes.Clin Pharmacol Ther. 2007; 82: 41-47Crossref PubMed Scopus (211) Google Scholar conversely, an URM produces higher levels with a potential to cause opioid toxicity.48Stamer U.M. Stüber F. Muders T. Musshoff F. Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication.Anesth Analg. 2008; 107: 926-929Crossref PubMed Scopus (143) Google Scholar Polymorphism in CYP3A4/5 may be of less clinical significance when considering opioid response.49Pirmohamed M. Park B.K. Cytochrome P450 enzyme polymorphisms and adverse drug reactions.Toxicology. 2003; 192: 23-32Crossref PubMed Scopus (120) Google Scholar Nonetheless, CYP3A4 activity varies up to 10 times and could be partly responsible for different dose requirements.50Haddad A. Davis M. Lagman R. The pharmacological importance of cytochrome CYP3A4 in the palliation of symptoms: review and recommendations for avoiding adverse drug interactions.Support Care Cancer. 2007; 15: 251-257Crossref PubMed Scopus (54) Google Scholar Opioids potentially affected are fentanyl (and related drugs, alfentanil, sufentanil), methadone, oxycodone and, to a lesser extent, buprenorphine. Although genetic variation can result in serious consequences, pharmacogenetic testing is not routine, partly because it is not cost-effective, e.g., the impact of testing in relation to warfarin dosing.51Kimmel S.E. French B. Kasner S.E. et al.COAG InvestigatorsA pharmacogenetic versus a clinical algorithm for warfarin dosing.N Engl J Med. 2013; 369: 2283-2293Crossref PubMed Scopus (605) Google Scholar, 52Pirmohamed M. Burnside G. Eriksson N. et al.EU-PACT GroupA randomized trial of genotype-guided dosing of warfarin.N Engl J Med. 2013; 369: 2294-2303Crossref PubMed Scopus (648) Google Scholar Thus, generally, close clinical monitoring is recommended for drugs with a major metabolic enzyme pathway affected by genetic polymorphism (see Table 3 and Appendix). However, in some settings, e.g., oncology, testing has been used to determine if an individual is likely to respond to a specific drug, e.g., cetuximab (colorectal cancer), trastuzumab (breast cancer), and dasatinib (acute lymphoblastic leukemia). Pharmacokinetic drug–drug interactions mediated through increased or decreased activity of CYP450 enzymes are common, but the resultant clinical impact is difficult to predict.30Wilkinson G.R. Drug metabolism and variability among patients in drug response.N Engl J Med. 2005; 352: 2211-2221Crossref PubMed Scopus (911) Google Scholar, 53Aeschlimann J. Tyler L. Drug interactions associated with cytochrome P-450 enzymes.J Pharmaceut Care Pain Symptom Control. 1996; 4: 35-54Crossref Scopus (2) Google Scholar, 54Johnson M.D. Newkirk G. White Jr., J.R. Clinically significant drug interactions.Postgrad Med. 1999; 105: 193-222Crossref PubMed Scopus (36) Google Scholar, 55Samer C.F. Lorenzini K.I. Rollason V. Daali Y. Desmeules J.A. Applications of CYP450 testing in the clinical setting.Mol Diagn Ther. 2013; 17: 165-184Crossref PubMed Scopus (255) Google Scholar Some drugs (inducers) increase the activity of specific CYP450 enzymes and others (inhibitors) decrease enzyme activity (see Table 7). When CYP450 inhibitors or inducers are co-administered with drugs that are already affected by genetic polymorphisms, they will either augment or mitigate the clinical effects of the genetic variation. Onset and offset of enzyme induction is gradual, possibly 2–3 weeks, because:•onset depends on drug-induced synthesis of new enzyme•offset depends on elimination of the enzyme-inducing drug and the decay of the increased enzyme sto" @default.
• W2022972328 created "2016-06-24" @default.
• W2022972328 creator A5009522619 @default.
• W2022972328 creator A5036367747 @default.
• W2022972328 creator A5041774156 @default.
• W2022972328 creator A5067945122 @default.
• W2022972328 creator A5076460433 @default.
• W2022972328 creator A5083234618 @default.
• W2022972328 date "2015-02-01" @default.
• W2022972328 modified "2023-10-18" @default.
• W2022972328 title "Variability in Response to Drugs" @default.
• W2022972328 cites W131869076 @default.
• W2022972328 cites W132786152 @default.
• W2022972328 cites W1508531867 @default.
• W2022972328 cites W1548404106 @default.
• W2022972328 cites W1564580398 @default.
• W2022972328 cites W1841069382 @default.
• W2022972328 cites W1965228291 @default.
• W2022972328 cites W1966702876 @default.
• W2022972328 cites W1968814844 @default.
• W2022972328 cites W1972280475 @default.
• W2022972328 cites W1974645621 @default.
• W2022972328 cites W1978743404 @default.
• W2022972328 cites W1983877031 @default.
• W2022972328 cites W1985327494 @default.
• W2022972328 cites W1985556537 @default.
• W2022972328 cites W1989956851 @default.
• W2022972328 cites W1994171421 @default.
• W2022972328 cites W1999055426 @default.
• W2022972328 cites W2001815145 @default.
• W2022972328 cites W2002555198 @default.
• W2022972328 cites W2005673243 @default.
• W2022972328 cites W2006015545 @default.
• W2022972328 cites W2006582768 @default.
• W2022972328 cites W2008263033 @default.
• W2022972328 cites W2012849584 @default.
• W2022972328 cites W2014405410 @default.
• W2022972328 cites W2016124588 @default.
• W2022972328 cites W2018655119 @default.
• W2022972328 cites W2019695588 @default.
• W2022972328 cites W2022797906 @default.
• W2022972328 cites W2026330543 @default.
• W2022972328 cites W2029660222 @default.
• W2022972328 cites W2034839664 @default.
• W2022972328 cites W2035217998 @default.
• W2022972328 cites W2036815814 @default.
• W2022972328 cites W2038673720 @default.
• W2022972328 cites W2039610177 @default.
• W2022972328 cites W2043527756 @default.
• W2022972328 cites W2044629340 @default.
• W2022972328 cites W2044951617 @default.
• W2022972328 cites W2045070031 @default.
• W2022972328 cites W2048865031 @default.
• W2022972328 cites W2050707213 @default.
• W2022972328 cites W2051746492 @default.
• W2022972328 cites W2057263347 @default.
• W2022972328 cites W2062168975 @default.
• W2022972328 cites W2062636686 @default.
• W2022972328 cites W2074524706 @default.
• W2022972328 cites W2079754266 @default.
• W2022972328 cites W2080822069 @default.
• W2022972328 cites W2081577644 @default.
• W2022972328 cites W2086185646 @default.
• W2022972328 cites W2088216581 @default.
• W2022972328 cites W2090910729 @default.
• W2022972328 cites W2092267763 @default.
• W2022972328 cites W2092679194 @default.
• W2022972328 cites W2093584791 @default.
• W2022972328 cites W2096329648 @default.
• W2022972328 cites W2103481781 @default.
• W2022972328 cites W2107948836 @default.
• W2022972328 cites W2115509509 @default.
• W2022972328 cites W2124448589 @default.
• W2022972328 cites W2124474534 @default.
• W2022972328 cites W2126977230 @default.
• W2022972328 cites W2128189669 @default.
• W2022972328 cites W2131612411 @default.
• W2022972328 cites W2134431157 @default.
• W2022972328 cites W2137643863 @default.
• W2022972328 cites W2138984037 @default.
• W2022972328 cites W2142291582 @default.
• W2022972328 cites W2143777566 @default.
• W2022972328 cites W2144980699 @default.
• W2022972328 cites W2157839219 @default.
• W2022972328 cites W2163483326 @default.
• W2022972328 cites W2163636362 @default.
• W2022972328 cites W2167401706 @default.
• W2022972328 cites W2409256593 @default.
• W2022972328 cites W4211214267 @default.
• W2022972328 cites W4254462900 @default.
• W2022972328 doi "https://doi.org/10.1016/j.jpainsymman.2014.10.003" @default.
• W2022972328 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25448823" @default.
• W2022972328 hasPublicationYear "2015" @default.
• W2022972328 type Work @default.
• W2022972328 sameAs 2022972328 @default.
• W2022972328 citedByCount "3" @default.
• W2022972328 countsByYear W20229723282017 @default.
• W2022972328 countsByYear W20229723282020 @default.

• next