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Principles of pharmacogenetics—implications for the anaesthetist

2004; Elsevier BV; Volume: 93; Issue: 3 Linguagem: Inglês

10.1093/bja/aeh200

1471-6771

Gabriella Iohom, D Fitzgerald, Anthony J. Cunningham,

Pharmaceutical studies and practices

'If it were not for the great variability among individuals, medicine might as well be a science and not an art.' Sir William Osler's observations in 189260Roses AD. Pharmacogenetics and the practice of medicine.Nature. 2000; 405: 857-865Crossref PubMed Scopus (700) Google Scholar reflect a perception of medicine over 100 years ago, highlighting the lack of available objective data to make decisions that are tailored to individual patients. One hundred years later, scientists are on the verge of being able to identify inherited differences between individuals, which may predict each patient's response to a particular drug. This ability will have undoubted benefits in the discovery, development, and delivery of new medicines. Sir William Osler, if he were alive today, would be forced to reconsider his view of medicine as an art not a science. Pharmacogenetics emerged as a discipline that attempted to understand the hereditary basis for differences in responsiveness or inter-individual variation to therapeutic agents.85West WL Knight EM Pradhan S Hinds TS. Interpatient variability: genetic predisposition and other genetic factors.J Clin Pharmacol. 1997; 37: 635-648Crossref PubMed Scopus (31) Google Scholar Variation in a drug effect may vary from 2- to 10-fold or 100-fold, even among members of the same family.35Keown PA Stiller CR Laupacis AL et al.The effects and side effects of cyclosporine: relationship to drug pharmacokinetics.Transplant Proc. 1982; 14: 659-661PubMed Google Scholar, 90Wu CY Benet LZ Herbert MF et al.Differentiation of absorption and first-pass gut and hepatic metabolism in humans: studies with cyclosporine.Clin Pharmacol Ther. 1995; 58: 492-497Crossref PubMed Scopus (342) Google Scholar Similar inter-patient variability is observed in the risk of adverse effects of a drug or a chemical.85West WL Knight EM Pradhan S Hinds TS. Interpatient variability: genetic predisposition and other genetic factors.J Clin Pharmacol. 1997; 37: 635-648Crossref PubMed Scopus (31) Google Scholar Pharmacogenetics has been defined as the study of variability in drug response as a result of heredity factors.52Nebert DW. Pharmacogenetics and pharmacogenomics: why is this relevant to the clinical geneticist?.Clin Genet. 1999; 56: 247-258Crossref PubMed Scopus (194) Google Scholar More recently, the term 'pharmacogenomics' has been introduced. While the former term is largely used in relation to variants in genes that influence drug response, the latter refers to changes in gene expression as a consequence of drug exposure.14Evans WE Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics.Science. 1999; 286: 487-491Crossref PubMed Scopus (2128) Google Scholar The value of an understanding of pharmacogenetics for the clinician is to enable optimum therapeutic efficacy; to avoid toxicity of those drugs whose metabolism is catalysed by polymorphic isoenzymes; and to contribute to the rational design of new drugs. Pharmacogenetics and pharmacogenomics cannot be understood without a grasp of basic medical genetics. Anaesthetists traditionally possess a basic knowledge of medical genetics to understand conditions such as malignant hyperthermia (MH) and atypical plasma cholinesterase. To optimally use anaesthetic agents, including opioids, a more comprehensive understanding of medical genetics will be required.15Fagerlund TH Braaten O. No pain relief from codeine …? An introduction to pharmacogenomics.Acta Anaesthesiol Scand. 2001; 45: 140-149PubMed Google Scholar A gene has its specific locus (from Latin, place) on a given chromosome. The gene for eye colour thus has its position in the human DNA determined by chromosome, and position on that chromosome. The gene, however, comes in various forms or alleles. For eye colour, the allele for blue eyes and the allele for brown eyes are two different alleles for the same gene. Although the expression is sometimes used, strictly speaking there is no such thing as a disease gene or a disease locus, only disease alleles. The classical definition of phenotype is 'the way you look'. If you have genes for blue eyes, that is your genotype. Your phenotype is 'being a blue-eyed person'. A phenotype could also be an enzyme activity above or below a certain value, or being able to metabolize a certain substance. Genetic research necessitates distinction between individuals at the DNA level. Different as we may be, we are identical for long stretches of DNA. Researchers usually attempt to identify gene markers, a short piece of DNA that can easily be detected. Two separate forms of markers exist, and the different forms can be used to tell the difference between individuals (or chromosomes, or parts of DNA). Finding a marker is like spotting the lanterns of a ship in the night. If you see one of the lanterns, you know you are not actually seeing the ship, but you can have a good guess as to where the ship is. When investigators find a marker that may be located close to a gene of interest, while the gene per se may not be located, substantial progress has been made. Some markers are single base mutations, others consist of repeats of short sequences where individuals differ in how many repeats they have, termed microsatellite markers. The word polymorphism comes from the Greek poly, several, and morphe, form. Polymorphism, thus, is something that can take one of several forms. A DNA polymorphism exists when individuals differ in their DNA sequence at a certain point in their genome. A normal form and a mutated form may represent such a difference. The mutated form can be a single base mutation, or variation over a short stretch of DNA. The term polymorphism is a general one. It is most often used to describe a marker that occurs in several forms—a marker polymorphism. Only 3% of DNA consists of coding sequences and in most regions of the genome, a polymorphism is of no clinical consequence. However, the term polymorphism is also used about a mutation inside a coding sequence, where the mutation might be causing disease. Single nucleotide polymorphisms (SNPs) are changes in a single base at a specific position in the genome, in most cases with two alleles. SNPs are found at a frequency of about 1:1000 bases in humans. By definition, the more rare allele should be more abundant than 1% in the general population.40Kruglyak L. The use of a genetic map of biallelic markers in linkage studies.Nature Genet. 1997; 17: 21-24Crossref PubMed Scopus (390) Google Scholar The relative simplicity of SNP genotyping technologies and the abundance of SNPs in the human genome have made them very popular in recent years.21Gut IG. Automation in genotyping of single nucleotide polymorphisms.Hum Mutat. 2001; 17: 475-492Crossref PubMed Scopus (169) Google Scholar Yet, there still is some debate about the usefulness of SNP markers compared with microsatellite markers for linkage studies, and how many SNP markers will have to be analysed for meaningful association studies.41Kruglyak L. Prospect for whole-genome linkage disequilibrium mapping of common disease genes.Nature Genet. 1999; 22: 139-144Crossref PubMed Scopus (1136) Google Scholar Several genotyping technologies have reached maturity in the last few years and are being integrated into large sale genotyping operations supported by automation. The choice of a technology for genotyping depends on whether a few different SNPs are to be genotyped in many individuals, or many different SNPs are to be genotyped in a few individuals.64Shi MM Bleavins MR de la Iglesia FA. Technologies for detecting genetic polymorphisms in pharmacogenomics.Mol Diagn. 1999; 4: 343-354Crossref PubMed Scopus (66) Google Scholar Although genotyping methods are very diverse, broadly, each method can be separated into two elements. The first element is a method for interrogating an SNP. This is a sequence of molecular biological, physical, and chemical procedures for the distinction of the alleles of an SNP, that is hybridization,79Tyagi S Bratu DP Kramer FR. Multicolor molecular beacons for allele discrimination.Nat Biotechnol. 1998; 16: 49-53Crossref PubMed Scopus (1137) Google Scholar primer extension,72Syvanen AC. From gels to chips: 'minisequencing' primer extension for analysis of point mutations and single nucleotide polymorphisms.Hum Mutat. 1999; 13: 1-10Crossref PubMed Scopus (275) Google Scholar oligonucleotide ligation,54Nilsson M Malmgren H Samiotaki M et al.Padlock probes: circularizing oligonucleotides for localized DNA detection.Science. 1994; 265: 2085-2088Crossref PubMed Scopus (610) Google Scholar and nuclease cleavage.55Parsons BL Heflich RH. Genotypic selection methods for the direct analysis of point mutations.Mutat Res. 1997; 387: 97-121Crossref PubMed Scopus (110) Google Scholar The second element is the actual analysis or measurement of the allele-specific products, that is by gel separation,63Schuber AP Michalowsky LA Nass GS et al.High throughput parallel analysis of hundreds of patient samples for more than 100 mutations in multiple disease genes.Hum Mol Genet. 1997; 6: 337-347Crossref PubMed Scopus (69) Google Scholar microarrays,7Brown PO Botstein D. Exploring the new world of the genome with DNA microarrays.Nature Genet. 1999; 21: 33-37Crossref PubMed Scopus (2015) Google Scholar mass spectrometry,22Haff L Smirnov IP. Single-nucleotide polymorphism identification assays using a thermostable DNA polymerase and delayed extraction MALDI-TOF mass spectrometry.Genome Res. 1997; 7: 378-388Crossref PubMed Scopus (213) Google Scholar flow cytometry,9Cai H White PS Torney D et al.Flow cytometry-base minisequencing: a new platform for high-throughput single-nucleotide polymorphism scoring.Genomics. 2000; 66: 135-143Crossref PubMed Scopus (116) Google Scholar etc. Often, very different methods share elements, like reading out a fluorescent tag in a plate reader, or the method of generating allele-specific products (i.e. by primer extension or oligonucleotide ligation), which can be analysed in different analysis formats.21Gut IG. Automation in genotyping of single nucleotide polymorphisms.Hum Mutat. 2001; 17: 475-492Crossref PubMed Scopus (169) Google Scholar A gene and a marker are said to be linked if they reside close to each other on the same chromosome. In linkage studies, a set of markers, with a known location on the genetic map, is used to track down a gene of unknown location. In a linkage study, the disease allele is not known, but merely manifests itself as disease in the person who carries it. The basic assumption is that if a certain disease allele and a certain marker allele are found together in a family, the two are physically close on the same chromosome. The statistical methods of linkage analysis calculate just how unlikely it would be to consistently find a marker allele and a disease allele together. If this turns out to be very unlikely to have occurred by chance, the alternative hypothesis of linkage of marker and disease gene is accepted. If a marker allele and a disease allele occur together consistently in a population, they are said to be in linkage disequilibrium. Genetic linkage studies have identified various loci on causative genes for malignant hyperthermia susceptibility (MHS).49McCarthy TV Quane KA Lynch PJ. Ryanodine receptor mutations in malignant hyperthermia and central core disease.Hum Mutat. 2000; 15: 410-417Crossref PubMed Scopus (304) Google Scholar Association studies exploit the fact that there may be linkage disequilibrium in the population. A study may start out with a large number of markers with a known location. A number of patients with a disease are examined for these markers. If a substantial majority of patients have the same markers, it is likely that the gene responsible for the disease is located close to the markers that the patients have in common. The apolipoprotein (apo) E4 genotype, for example, is strongly associated with Alzheimer's disease, representing a susceptibility gene, but is not necessarily causative of the disease, meaning that having this genotype is not generally sufficient to cause Alzheimer's.57Pimstone S. Old-fashioned genetics remains genomics' best friend.PharmaTech. 2002; 2: 88-90Google Scholar Classically, pharmacologists have concentrated on genetic variability that alters drug metabolizing enzymes to explain variation in pharmacokinetic responses to drug therapy. However, it is now apparent that genetic variability can affect many other important proteins such as transporter proteins and receptors. Thus, pharmacogenetics is best defined as the study of genetic variations that cause a variable drug response and includes the genetic polymorphism of drug transporters, drug metabolizing enzymes, and drug receptors. Genetic determinants of drug response can be divided into two types: (i) those characterized by alteration in drug metabolism, such as those as a result of differences in levels of N-acetyltransferase (NAT) or atypical plasma cholinesterase and (ii) those characterized by alteration in pharmacodynamics. Inter-individual variation in therapeutic drug response and toxicity is most often a result of variability in drug metabolism rather than pharmacodynamics.34Kalow W. Pharmacogenetics: its biological roots and the medical challenge.Clin Pharmacol Ther. 1993; 54: 235-241Crossref PubMed Scopus (41) Google Scholar Observed genetic variability in drug metabolism can be either monogenic or polygenic. When the variability is a result of single genes, the term monogenic is used. When genes, which individually produce small effects but collectively lead to significant effects are involved, the term polygenic is used.30Inaba T Nebert DW Burchell B et al.Pharmacogenetics in clinical pharmacology and toxicology.Can J Physiol Pharmacol. 1995; 73: 331-338Crossref PubMed Scopus (33) Google Scholar Much pharmacogenetic research focuses on the monogenic variants of drug-metabolizing enzymes and on polymorphisms (i.e. variants that exist in at least 1% of the population).1Arias TD Jorge LF Barrantes R. Uses and misuses of definitions of genetic polymorphism. A perspective from population pharmacogenetics.Br J Clin Pharmacol. 1991; 31: 117-118Crossref PubMed Scopus (18) Google Scholar Such genes generally affect drug biotransformation by altering the amount or function of an enzyme. The existence of such polymorphisms explains why drug metabolism shows a polymodal distribution. In other words, patient populations can be divided into two groups (or phenotypes) according to their abilities to metabolize specific probe drugs. Poor or slow metabolizers have deficient metabolizing ability; in contrast, extensive metabolizers metabolize drugs more rapidly and may need higher doses to produce a therapeutic response.18Gonzalez FJ Idle JR. Pharmacogenetic phenotyping and genotyping. Present status and future potential.Clin Pharmacokinetics. 1994; 26: 59-70Crossref PubMed Scopus (189) Google Scholar Drug metabolism is divided into phase I and phase II reactions. Phase I reactions, including oxidation, reduction, and hydrolysis, introduce a polar group into the molecule, whereas phase II reactions conjugate an endogenous hydrophilic substance with the drug, resulting in more water-soluble compounds. Oxidation, a major route of metabolism for many drugs, is catalysed by the mixed function oxidase system, which comprises cytochrome P450 (CYP) enzymes. P450 enzymes are found in virtually all tissues with the highest concentration in the endoplasmic reticulum of the liver.66Slaughter RL Edwards DJ. Recent advances: the cytochrome P450 enzymes.Ann Pharmacother. 1995; 29: 619-624Crossref PubMed Scopus (247) Google Scholar, 73Tanaka E. Update: genetic polymorphism of drug metabolizing enzymes in humans.J Clin Pharmacy Therapeut. 1999; 24: 323-329Crossref PubMed Scopus (56) Google Scholar The recommended nomenclature of cytochrome P450 isoenzymes is based upon grouping enzymes and genes into families and subfamilies with the prefix CYP denoting cytochrome P450. Families are characterized by an Arabic number (i.e. CYP2) and subfamilies are indicated by a letter (i.e. CYP2D). The individual genes coding for one specific isoenzyme are denoted by a second Arabic number after the letter in italics, that is CYP2D6. Members of the same enzyme/gene family may exhibit more than 40% identity in amino acid sequences, while a subfamily consists of those sharing greater than 55% sequence identity (Fig. 1).67Spatzeneger M Jaeger W. Clinical importance of hepatic cytochrome P450 in drug metabolism.Drug Metabolism Rev. 1995; 27: 397-417Crossref PubMed Scopus (237) Google Scholar Several P450 isoenzymes are involved in human hepatic drug metabolism. Their activities may be inhibited or induced by drugs or environmental xenobiotics. Their activity is also determined genetically as a consequence of common polymorphisms. The activity of cytochrome P450 enzymes can be measured by administration of a probe drug, known to be selectively metabolized by the CYP enzyme under study, followed by measurement of the metabolic ratio (the ratio of the drug dosage or unchanged drug to metabolite in serum or urine). However, such phenotyping takes into account all factors influencing the activity of the enzyme, such as the presence of a competing substrate, and is sensitive to the overall process of drug metabolism. Genotyping involves identification of defined genetic mutations on the CYP genes that give rise to the specific drug metabolism phenotype. These mutations include genetic alterations that lead to over-expression (gene duplication), absence of an active protein product (null allele), or production of a mutant protein with diminished catalytic capacity (inactivating allele). Genotyping methods require small amounts of blood or tissue, are not affected by underlying disease or by drugs taken by the patient, and need to be done only once in a lifetime. By screening for genetic variants, an individual's drug metabolism phenotype can be characterized.84van der Weide J Steijns LSW. Cytochrome P450 enzyme system: genetic polymorphisms and impact on clinical pharmacology.Ann Clin Biochem. 1999; 36: 722-729Crossref PubMed Scopus (111) Google Scholar Besides the P450 genes, other phase I enzymes are polymorphic, such as alcohol dehydrogenases (ADH) and acetaldehyde dehydrogenase (ALDH), as well as dihydropyrimidine dehydrogenase (DPD). With respect to the first two enzymes, the clearance of ethanol is significantly affected, ADHB2 giving a higher rate of ethanol metabolism and ALDH2 polymorphism influencing acetaldehyde metabolism. Poor metabolizers for ALDH2 develop flush reactions and anti-abuse like side-effects when drinking ethanol and the number of alcoholics with this genotype is lower. A polymorphism relevant to treatment with anticancer drugs is present in DPD. 5-Fluorouracil is metabolized by this enzyme. Subjects with impaired enzyme activity caused by inactivating gene mutations suffer from a severely increased risk of adverse reactions, including myelotoxicity and neurotoxicity following 5-fluorouracil administration.31Ingelman-Sundberg M. Pharmacogenetics: an opportunity for a safer and more efficient pharmacotherapy.J Intern Med. 2001; 250: 186-200Crossref PubMed Scopus (206) Google Scholar Several enzyme families directly conjugate drugs or their oxidative metabolites. There are 15 human uridine diphosphate glucuronosyltransferases (UGTs), broadly classified into the UGT1 (phenol/bilirubin) and UGT2 (steroid/bile) families.78Tukey RH Strassburg CP. Human UDP-glucuronosyltransferases: metabolism, expression, and disease.Annu Rev Pharmacol Toxicol. 2000; 40: 581-616Crossref PubMed Scopus (1288) Google Scholar, 87de Wildt SN Kearns GL. Leeder JS. et al.Glucuronidation in humans.Clin Pharmacokinet. 1999; 36: 439-452Crossref PubMed Scopus (356) Google Scholar Considerable polymorphism in glutathione S-transferase (GST) expression has been described and associated with susceptibility to disease, particularly cancer and asthma (both as disease-causing and disease-modifying factors).13Eaton DL Bammler TK. Concise review of the glutathion S-transferases and their significance to toxicology.Toxicol Sci. 1999; 49: 156-164Crossref PubMed Scopus (547) Google Scholar, 23Hayes JD Strange RC. Glutathion S-transferase polymorphisms and their biological consequences.Pharmacology. 2000; 61: 154-166Crossref PubMed Scopus (818) Google Scholar NAT was the first drug metabolizing enzyme for which a genetic polymorphism was discovered (slow and fast acetylators). Slow acetylators show a greater therapeutic response than fast acetylators to several drugs (i.e. isoniazid, hydralazine) but may be more susceptible to side-effects. There are two human NATs, NAT1 and NAT2, with discrete but overlapping substrate specificities. Although there are polymorphisms in NAT1, it is the genetic variability in NAT2 that is responsible for the slow-acetylator phenotype.24Hein DW Doll MA Fretland AJ et al.Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms.Cancer Epidemiol Biomarkers Prev. 2000; 9: 29-42PubMed Google Scholar Sulfotransferases (STs) catalyse the elimination of acetaminophen and morphine in neonates.53Negishi M Pedersen LG Petrotchenko E et al.Structure and function of sulfotransferases.Arch Biochem Biophys. 2001; 390: 149-157Crossref PubMed Scopus (267) Google Scholar The clinical implications of polymorphism of drug metabolizing enzymes are drug toxicity and therapeutic failure. The clinical relevance, however, depends on the therapeutic ratio of the drug.77Tucker GT. Clinical implications of genetic polymorphism in drug metabolism.J Pharmacy Pharmacol. 1994; 46: 417-424PubMed Google Scholar The influence of the genetic make-up of an individual is not limited to drug metabolism. Genetic variability influences drug absorption and this forms the basis for slow and rapid drug absorption. Most drugs or drug metabolites enter the cells by passive diffusion. Some drugs are actively transported by transporter proteins, of which membrane transporters may play a key role. These transmembrane transporters are members of the large protein family known as ABC (adenosine triphosphate binding cassette) proteins.39Klein I Sarkadi B Varadi A. An inventory of the human ABC proteins.Biochim Biophys Acta. 1999; 1461: 237-262Crossref PubMed Scopus (511) Google Scholar Although they do not catalyse biotransformation per se, they nonetheless markedly affect drug bioavailability and can act in conjunction with intracellular drug metabolizing enzymes. P-Glycoprotein (also called multi-drug resistant P-glycoprotein, MDR1) is the first cloned and best-characterized ABC protein.61Schinkel AH. The physiological function of drug-transporting P-glycoproteins.Semin Cancer Biol. 1997; 3: 161-170Crossref Scopus (440) Google Scholar, 92Zhang Y Benet LZ. The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein.Clin Pharmacokinet. 2001; 40: 159-168Crossref PubMed Scopus (490) Google Scholar At the blood–brain barrier, P-glycoprotein may influence the uptake of substrates into the brain: high P-glycoprotein levels may limit the uptake of sufficient amounts of the desired drug into the brain, and reduced P-glycoprotein activity could lead to abnormally increased accumulation in the brain and undesired side-effects of a drug.6Brinkmann U. Functional polymorphism of the human multidrug resistance (MDR1) gene: correlation with P glycoprotein expression and activity in vivo.Novartis Found Symp. 2002; 243: 207-210Crossref PubMed Google Scholar A second subfamily of ABC proteins is the multi-drug resistance-associated proteins, also known as the multi-specific organic anion transporter.5Borst P Evers R Kool M et al.A family of drug transporters: the multidrug resistance-associated proteins.J Natl Cancer Inst. 2000; 92: 1295-1302Crossref PubMed Scopus (1543) Google Scholar The first protein to be discovered in this category was MRP1, whose over-expression is responsible for the majority of non-P-glycoprotein-mediated multi-drug resistance. There are seven currently known MRPs with uncertain clinical significance. Rifampicin is known to induce human MRP2.17Fromm MF Kauffmann HM Fritz P et al.The effect of rifampin treatment on intestinal expression of human MRP transporters.Am J Pathol. 2000; 157: 1575-1580Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar When examining the response to a drug, the most obvious target for genetic studies of drug response is the receptor. Genetic variability influences interactions with receptors and this forms the basis for poor or efficient receptor interactions. The polymorphisms in genes encoding receptors relevant to drug treatment of different diseases cause widespread variation in sensitivity to many drugs. For example, individuals with a mutation in the gene encoding prothrombin may have increased risk of cerebral vein thrombosis when using oral contraceptives. Other examples of the impact of genetic polymorphisms include: angiotensin converting enzyme (ACE) and its sensitivity to ACE inhibitors; β-adrenergic receptors and their sensitivity to β-agonists in asthmatics; and 5 hydroxytryptamine receptors and the response to certain neuroleptics.15Fagerlund TH Braaten O. No pain relief from codeine …? An introduction to pharmacogenomics.Acta Anaesthesiol Scand. 2001; 45: 140-149PubMed Google Scholar Mutations in cardiac potassium channel genes such as HERG (human ether-a-go-go-related gene) and KvLQT1 (chromosome 11 linked LQT gene) may both give susceptibility to drug-induced long QT syndrome, or KCNE2 (a potassium gene encoding MinK-related peptide-1, MiRP1) may give susceptibility to drug-induced arrhythmias. All are of clinical relevance to an anaesthetist.15Fagerlund TH Braaten O. No pain relief from codeine …? An introduction to pharmacogenomics.Acta Anaesthesiol Scand. 2001; 45: 140-149PubMed Google Scholar Pharmacogenomics is the research activity, which at the genome level, aims to identify disease genes and new drug response markers.31Ingelman-Sundberg M. Pharmacogenetics: an opportunity for a safer and more efficient pharmacotherapy.J Intern Med. 2001; 250: 186-200Crossref PubMed Scopus (206) Google Scholar The role of pharmacogenetics is increasingly recognized by the pharmaceutical industry with research programmes directed at drug discovery and development.93Zuhlsdorf MT. Relevance of pheno- and genotyping in clinical drug development.Int J Clin Pharmacol Ther. 1998; 36: 607-612PubMed Google Scholar Candidate drugs whose metabolism may involve polymorphic pathways may be screened out. Pharmacogenetic data may be used either to design better compounds or to help plan clinical studies. Screening volunteers and patients included in clinical trials may become necessary to minimize adverse events and optimize efficacy. Clinical investigations in various populations will help clarify inter-ethnic differences in drug disposition and response to a given drug. Knowledge of pharmacogenetics should help reduce the time and cost associated with new drug development. Clinical experience suggests that there is great heterogeneity in anaesthetic requirements in the way patients recover from uncomplicated anaesthesia, as well as their requirements for postoperative analgesia. Some of these differences can be explained by genetically determined differences in transport proteins, in drug targets and in enzyme functions. It is also important to know to what extent environmental factors (such as smoking, diet, and other drugs) interact with genetic factors to modulate drug effects. Recovery from general anaesthesia is dependent on factors governing drug sensitivity and drug disposition. Recovery from a single dose of i.v. anaesthetic agent is dependent on redistribution, whereas recovery after a prolonged infusion is progressively more dependent on metabolism and elimination of the drugs.28Hughes MA Glass PS Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs.Anesthesiology. 1992; 76: 334-341Crossref PubMed Scopus (612) Google Scholar Aging as well as environmental factors may influence drug dynamics. Both alcohol and tobacco play an important role in determining the degree of liver enzyme induction, which determines the rate of metabolism of some medications, including volatile anaesthetic agents, thus influencing outcome from anaesthesia.71Sweeney BP. Why does smoking protect against PONV?.Br J Anaesth. 2002; 89: 1-4Abstract Full Text Full Text PDF Scopus (48) Google Scholar Genetic polymorphisms in metabolizing enzymes become relevant if: they are responsible for 50% or more of the clearance of a drug; when using drugs with a steep dose–response curve and a narrow therapeutic window; and when using drugs whose activity depends upon a metabolite formed by a polymorphic enzyme. Inherited deficiency/reduced effect of plasma cholinesterase will result in prolonged muscle relaxation after succinylcholine.68Stockley IH. Neuromuscular blocker and anaesthetic drug interactions.in: Stockley IH Drug Interactions. Pharmaceutical Press, London1998: 722-756Google Scholar This was the first documented example of inherited variations in anaesthetic drug effects. The level and quality of plasma cholinesterase activity (acylcholine-acylhydrolase E.C.1.1.8, butyrylcholinesterase (BChE)) in a patient determines the duration of action of succinylcholine and mivacurium.33Jensen FS Schwartz M Viby-Mogensen J. Identification of human plasma cholinesterase variants using molecular biological techniques.Acta Anaesthesiol Scand. 1995; 39: 142-149Crossref PubMed Scopus (37) Google Scholar Genetic variation is one of several factors determining the activity of cholinesterase in plasma. The expansion from only fo