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Phenotyping of in Infants and Children: Potentials and Problems

Anders Rane, MD, PhD

ABBREVIATION. PM, poor metabolizer. cient in their metabolism of a variety of drugs (Table 3). The CYP2D6 polymorphic metabolism pattern involved many important groups of drugs, eg, sev- enetic polymorphism in drug-metabolizing eral ␤-adrenoceptor-blocking agents,2–4 antidepres- enzymes is a predominant cause of variability sants,5 and opiates.6–8 Gin drug metabolism, along with physiologic, At present, little is known about the develop- pathophysiologic, and environmental factors (Table ment of the extensive metabolizer phenotype dur- 1). Such polymorphisms are of interest from a basic ing ontogenesis. In vitro studies in human fetal biomedical, as well as a clinical, point of view, be- liver microsomes in our laboratory have revealed cause differences in treatment outcome and adverse that the N-demethylation of codeine and dextro- drug reactions have been associated with the differ- precedes the development of the O- ent phenotypes. demethylation reaction.9 Whereas the N-demethyl- Increased knowledge in this field should also be of ation is catalyzed by the nonpolymorphic CYP3A, great interest in pediatric drug therapy. However, the O-demethylation of these drugs is catalyzed by there is almost no information about the maturation CYP2D6. Studies by Trelyuer et al10 indicate that of polymorphic traits during ontogenesis. This issue the CYP2D6 enzyme is expressed in a minority of has therapeutic implications in pediatrics, first, be- liver specimens from late gestational period or cause several drug substrates of the polymorphic from newborn infants. The gene expression of this enzymes also are used in infants and children, and enzyme seems to precede the formation of the second, because for many such drugs, the treatment enzyme protein. Only in adulthood is there a pos- results may not be monitored by objective param- itive correlation between mRNA and enzyme pro- eters. tein, suggesting a transcriptional regulation in A number of polymorphisms in drug metabolizing adults. Trelyuer et al10 found that the catalytic in enzymes have been discovered in the last few vitro activity of CYP2D6 developed postnatally decades (Table 2). The cytochrome P450 (CYP) fam- over a period of several months. ily is the major enzyme system for oxidation of drugs. The clinically most important polymorphisms in this family include the debrisoquine/sparteine THE CYTOCHROME P4502C19 (MEPHENYTOIN- type in the CYP2D6 enzyme and the mephenytoin TYPE) POLYMORPHISM type in the CYP2C19 enzyme. They are based on The polymorphism was discovered in studies of detrimental mutations in the enzyme genes. Pharma- the kinetics of the antiepileptic drug mepheny- cogenetic polymorphisms also have been described toin.11 The CYP2C19 enzyme catalyzes the oxida- in phase II enzymes, eg, N-acetyl transferase, which tion of many psychoactive drugs, antiepileptics, was among the first to be discovered. Other poly- and so forth (Table 4). It is deficient in 2% to 5% of morphisms have been described for members of the whites.12 Studies in different populations have re- glutathione S-transferase enzyme family, but the vealed ethnic differences in the prevalence of the clinical importance of these for drug therapy is not deficient. PM phenotype. Approximately 15% to fully understood. 20% of Chinese and Japanese individuals are PMs.13,12 The enzyme deficiency is inherited as an autosomal recessive trait. No studies on this poly- THE CYP2D6 (DEBRISOQUINE/SPARTEINE) morphism during human development have been POLYMORPHISM found. This polymorphism is inherited as an autosomal recessive trait.1 Homozygous mutated individuals are denoted as poor metabolizers (PM) and are defi- THE N-ACETYL TRANSFERASE POLYMORPHISM Adult subjects are grouped into slow or rapid From the Department of Clinical Pharmacology, University Hospital, Upp- acetylators according to their capacity to acetylate sala, Sweden. isoniazid, sulfonamides, dapsone, or other probe Received for publication Mar 30, 1999; accepted Mar 31, 1999. drugs of this enzyme. The frequency of slow acety- Address correspondence to Anders Rane, MD, PhD, Department of Clinical Pharmacology, University Hospital, S-751 85 Uppsala, Sweden. lators varies widely among different ethnic groups, 14,15 Ͻ PEDIATRICS (ISSN 0031 4005). Copyright © 1999 by the American Acad- from 50% to 70% in whites to 25% in the Japa- emy of Pediatrics. nese population.14

640 PEDIATRICS Vol. 104Downloaded No. 3 September from www.aappublications.org/news 1999 by guest on September 24, 2021 TABLE 1. Causes of Variation in Drug Elimination The maturation of caffeine acetylation was stud- 20 Variation in renal (small at normal kidney function) ied subsequently by Pariente-Kayat et al using Variation in liver metabolism (significant, even at normal liver caffeine as probe drug. They included 54 children, function) 8 to 447 days of age, who were admitted to hospital Environmental factors for minor diseases. A group of 5 children with diet pollutants Pierre Robin syndrome also was included. The , tobacco, etc cumulative percentage of rapid acetylators in- drugs creased as a function of age. The plateau still was Age not achieved at l5 months of age, as assessed by the Heredity (monomorphic and/or polymorphic variation) AFMU/1X and AFMU/AFMU ϩ1U, ϩ1X, ϩ7U, ϩ1.7X ratios. It was concluded that acetylation status cannot be determined with certainty before Diverging data on the maturation of the rapid age 15 months. acetylation trait have been published. The rapid acet- Sulfadimidine also has been used as probe drug ylation phenotype is expressed when none or only in phenotyping acetylation rate.21 With this drug, a 15 one allele of the NAT2 gene carries a mutation. We significantly higher proportion (83%) of newborn investigated the in vitro acetylation of 7-amino-clon- infants belonged to the slow acetylator phenotype azepam in human fetal and adult liver prepara- compared with adults (50%). Szorady et al21 partly 16 tions. Whereas the adult enzyme preparations were ascribed this difference to deficient dietary intake possible to classify in slow and rapid acetylators, no of pantotenic acid, which is required for coenzyme such dichotomy was observed in the fetal enzyme A in the reaction. Obviously, other reasons also preparations. may contribute to the age-dependent difference. However, the fetal enzyme may be very active It is concluded that the slow phenotype predomi- 17 toward certain substrates. Meisel et al found that nates in newborn infants and infants during the first the fetal liver enzyme activity (gestational week 9 year. Slow postnatal maturation of the rapid acety- to 12) was close to 50% of the adult fast acetylation lation phenotype may result in higher sensitivity of rate using procainamide as substrate. We have no such infants to pharmacologic and toxic effects of explanation for the apparent discrepancy between drugs that are substrates of the N-acetyl transferase the results other than the possibility that different (Table 5). Uncritical use of these drugs may be a enzymes may be involved in the two reactions. potential risk. Several confounding factors are possible in exper- iments with human fetal tissue specimens. The post- mortem enzyme degradation may vary among liver specimens. The effect of gestational age also may CONCLUSIONS AND PERSPECTIVE conceal a possible in vitro polymorphism. And fi- As in adults, the variation in drug metabolism in nally, the endocrine influence of the pregnant infants and children is based on constitutional, woman may contribute to the suppression of a poly- genetic, and environmental factors. The existence morphic enzyme expression, as may postnatal con- of drug-metabolic polymorphisms gives an addi- formational changes in the enzyme protein, as sug- tional dimension to the variation, which is clini- gested by Cohen and Weber.18 cally important in the treatment with a variety of Our in vitro results are consistent with attempts widely used drugs. Inasmuch as many of these to phenotype infants and children with caffeine as drugs are used in infants and children, the pheno- probe drug of the N-acetyl transferase 2.19 In a typic expression should be of even greater interest group of 14 infants, it appeared that all but one in these groups because effects and side effects of (the oldest) were slow acetylators, using an anti- drugs in children are often not possible to monitor mode of 0.4. One infant was identified as a slow by objective means. The limited information about acetylator at age 54 days, but turned into a rapid the functional maturation of the polymorphic en- acetylator phenotype at age 7 months. Carrier et zymes should fuel increasing interest in this field. al19 concluded that the N-acetyl transferase is im- More information is needed to minimize the risk of mature and that caffeine acetylation phenotype therapeutic hazards in this age group. There are cannot be determined with certainty in infants several apparent indications for phenotyping in younger than age 1 year. clinical drug therapy (Table 6). If an enzyme path-

TABLE 2. Some Polymorphisms in Drug-metabolizing Enzymes Enzyme Function Discovered Through Genophenotyping* Ref. No. Pseudocholinesterase Hydrolysis Pronounced clinical effect (apnea) of Kalow and Genest, 1957 22 sucinylcholin/suxamethonium N-acetyl-transferase Acetylation High concentration of isoniazid Price Evans et al 1960 23 Cytochrome P450D6 Oxidation Ortostatic hypotension of debrisoquine Maghoub et al 1975 1 Cytochrome P4502C19 Oxidation Pronounced sensitivity to mephenytoin Ku¨pfer and Preisig 1984 11 GSTM1 Conjugation — Seidegard et al 1986 24 GSTT1 Conjugation — Pemble et al 1994 25 GSTP1 Conjugation — Satoh et al 1985 26

Downloaded from www.aappublications.org/news by guest on September 24, 2021 SUPPLEMENT 641 TABLE 3. Drug Substrates of the Polymorphic Cytochrome measurable by objective methods, phenotyping P450 (CYP) 2D6 Enzyme may help to individualize the dose according to Cardiovascular agents ␤-adrenoceptor blockers the patient’s need. Low therapeutic index, Debrisoquine Metoprolol problems, unexpected outcome of therapy, and so Sparteine forth, should also increase the motivation for phe- Propafenone Timolol Antiemetics notyping. Additional indications to phenotype in- Tropisetron fants and children are age-dependent kinetics of Neuroleptics antidepressants drugs that are polymorphically metabolized. / Chlorpormazine desmethylclomipramine REFERENCES Remoxipride impramine/ 1. Maghoub A, Idle JR, Dring LC, Lancaster R, Smith RL. Polymorphic Zuklopenitoxol Despiramine hydroxylation of debrisoquine in man. Lancet. 1977;ii:584–586 Opiates Other anatidepressants 2. 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642 SUPPLEMENT Downloaded from www.aappublications.org/news by guest on September 24, 2021 human serum cholinesterase. Determination of dibucaine numbers. Can 25. Pemble S, Schroeder KR, Spenser SR, et al. Human glutathione S- J Biochem Physiol. 1957;35:339–346 transferase theta (GSTT1): cDNA cloning and the characterization of a 23. Price Evans DA, Manley KA, McKusick VA. Genetic control of isoniazid genetic polymorphism. Biochem J. 1994;300:271–276 metabolism in man. Br Med J. 1960;2:485–491 26. Satoh K, Kitahara A, Soma Y, Inaba Y, Hatayama I, Sata K. Purification 24. Seidegard J, Pero RW, Miller DJ, Beattie EJ. A glutathione transferase in induction and distribution of placental glutathione S-transferase: a new human leukocytes as a marker for the susceptibility to lung cancer. marker enzyme for preneoplastic rat chemical carcinogenesis. Proc Natl Carcinogenesis. 1986;7:751–753 Acad Sci USA. 1985;82:3964–3968

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 1999 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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