Relevance of UDP-glucuronosyltransferase polymorphisms for drug dosing: A quantitative systematic review.
UDP-glucuronosyltransferases (UGT) catalyze the biotransformation of many endobiotics and xenobiotics, and are coded by polymorphic genes. However, knowledge about the effects of these polymorphisms is rarely used for the individualization of drug therapy. Here, we present a quantitative systematic review of clinical studies on the impact of UGT variants on drug metabolism to clarify the potential for genotype-adjusted therapy recommendations. Data on UGT polymorphisms and dose-related pharmacokinetic parameters in man were retrieved by a systematic search in public databases. Mean estimates of pharmacokinetic parameters were extracted for each group of carriers of UGT variants to assess their effect size. Pooled estimates and relative confidence bounds were computed with a random-effects meta-analytic approach whenever multiple studies on the same variant, ethnic group, and substrate were available. Information was retrieved on 30 polymorphic metabolic pathways involving 10 UGT enzymes. For irinotecan and mycophenolic acid a wealth of data was available for assessing the impact of genetic polymorphisms on pharmacokinetics under different dosages, between ethnicities, under comedication, and under toxicity. Evidence for effects of potential clinical relevance exists for 19 drugs, but the data are not sufficient to assess effect size with the precision required to issue dose recommendations. In conclusion, compared to other drug metabolizing enzymes much less systematic research has been conducted on the polymorphisms of UGT enzymes. However, there is evidence of the existence of large monogenetic functional polymorphisms affecting pharmacokinetics and suggesting a potential use of UGT polymorphisms for the individualization of drug therapy.
Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany; Translational Pharmacology, University of Bonn Medical Faculty, Germany. Electronic address: julia.stingl@bfarm.de.
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JC
Stingl
Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Germany.
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H
Bartels
Department of Psychiatry and Psychotherapy III, University of Ulm, Germany.
R
R
Viviani
Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany.
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ML
Lehmann
Institute of Clinical Pharmacology, University of Göttingen, Germany.
J
J
Brockmöller
D000700:Analgesics / Q000378:metabolism / Q000493:pharmacokinetics; D019380:Anti-HIV Agents / Q000378:metabolism / Q000493:pharmacokinetics; D000959:Antihypertensive Agents / Q000378:metabolism / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000378:metabolism / Q000493:pharmacokinetics; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000378:metabolism*; D010599:Pharmacokinetics; D011110:Polymorphism, Genetic; D011619:Psychotropic Drugs / Q000378:metabolism / Q000493:pharmacokinetics; D014530:Uridine Diphosphate / Q000378:metabolism*
D000700:Analgesics; D019380:Anti-HIV Agents; D000959:Antihypertensive Agents; D000970:Antineoplastic Agents; D004364:Pharmaceutical Preparations; D011619:Psychotropic Drugs; D014530:Uridine Diphosphate; D014453:Glucuronosyltransferase
A; AUC; Adenine; Afr; Africans; As; Asians; C; C(t); Cauc./Cau; Caucasians; Cl; Cl(Het); Cl(Hom); Cl(Wt); Clearance; Clearance of the heterozygous alleles; Clearance of the homozygous alleles; Clearance of the wild-type alleles; Cyclosporine; Cytosine; Drug metabolism; E(Het); E(Hom); E(Wt); G; Guanine; HIV; Het; Heterozygous; Hom; Homozygous; MD; NSAID(s); PK; PharmGKB; Pharmacogenetics; Pharmacogenetics-based dose adjustments; Pharmacogenomics Knowledgebase; Polymorphism; Reference; SD; SN-38; Sign; Significant; Sirolimus; T; Tacrolimus; Thymine; UDP; UDP-glucuronosyltransferase; UDP-glucuronosyltransferases; UGT; UGT1A1; Wt; area under the curve; cyc; genotype effects of the heterozygous alleles; genotype effects of the homozygous alleles; genotype effects of the wild-type alleles; human immunodeficiency virus infection; i.e.; id est (that is); metabolite of Irinotecan; multiple dose; non-steroidal antiinflammatory drugs; pharmacokinetics; ref./Ref; single dose; sir; tac; trough concentration; uridine diphosphate; wild type