although the extent of the decrease varies somewhat between reports. For younger age groups, binding affinity appears to be substrate specific. Thus, fetal serum albumin binds salicylate with lower avidity than adult serum albumin (association constants are 1.7-2.9 x 105 M"1 vs. 4.0 x 105 M"1), whereas it binds bilirubin more strongly (association constants 5.2 x 107 M"1 vs. 2.4 x 107 M"1).
For healthy elderly persons, in contrast to infants of age 1 year or younger, there is little conclusive evidence that dosage regimens of orally administered drugs, as recommended by Thummel and colleagues,21 need be altered for expected changes in plasma protein binding associated with advancing age.22
During the 1950s, a series of therapeutic disasters involving the administration of water-soluble preparations of vitamin K,23 sulfonamides,24 and chloramphenicol25 to premature and newborn infants occurred at several pediatric centers. Careful study of these events prompted investigators to propose inefficient glucuronidation of vitamin K derivatives and chloramphenicol and inefficient acetylation of sulfonamides as factors responsible for these adverse drug reactions. From these studies, and additional studies in immature animals, the delayed development of drug-metabolizing enzymes during the perinatal period was suggested to be a phenomenon of general significance.2 Since then, metabolic biotransformation has been amply demonstrated to be a major determinant of the pharmacokinetics of drugs (see pp. 18-50), usually by increasing the polarity of a drug to hasten its elimination through the action of Phase I enzymes that catalyze oxidation, reduction, and hydrolysis and Phase II enzymes that attach moieties such as glucuronic acid, acetate, sulfate, glutathione, and glycine to the drug molecule or its metabolites.
A total of 57 cytochrome P450 genes distributed among nine gene families of the Phase I cytochrome P450 superfamily of genes have been identified in humans (see p. 31).26,27 Among these, three families, CYP1, CYP2, and CYP3, as well as at least 24 individual enzymes they encode, dominate the biotransformation of therapeutic drugs and toxicants.28 Studies of the content, activity, and, more recently, gene expression are beginning to provide insight into the complex patterns of developmental change of Phase I enzymes accompanying early growth and development.
Within the CYP3 family, CYP3A enzymes metabolize more therapeutics and toxicants than the CYP1 and CYP2 families. CYP3A4 and CYP3A5 gene products account for about 30-40% of the total cytochrome P450 in adult liver and intestine. CYP3A7, the predominant fetal form of CYP3A, is uniquely expressed in fetal liver as early as 50-60 days of gestation. CYP3A7 expression continues through the perinatal period after which it declines progressively, reaching undetectable levels by about 1 year of age. CYP3A7 has been considered a fetus-specific enzyme, but it has been shown more recently to be expressed in adult human livers carrying the CYP3A71C allele by Sim and colleagues.29 CYP3A4/3A5 expression begins by about 1 week after birth, reaches 30% of adult levels by 1 month of age, and a maximum during childhood.30,31 The clearance of the narcotic analgesic fentanyl is 11.5 ml/kg/min at 33 weeks gestation, about 30% of its value in term infants, provides a measure of developmental changes in CYP3A431 (Figure 4.1A).
Members of the CYP1 and CYP2 families of enzymes exhibit various matu-rational patterns. By 1-3 months after birth, CYP1A2 has reached full adult activity, while CYP2C9, CYP2C19, and CYP2D6 have reached less than 20% of adult activities. At 3-5 years of age, CYP1A2 has twice the adult activity, while CYP2C9 and CYP2C19 exceed 100% of adult activity by 50-60%. At puberty, activities of these three enzymes have decreased to adult levels.
The flavin-containing monoxygenases (FMOs), encoded by a six-member gene family, is a Phase I gene involved in oxidative metabolism of xenobiotics containing nitrogen, sulfur, selenium, and phosphorus. One member of this family, FM03, has been identified as genetically defective and causative of the fish malodor syndrome (see Appendix A). The human hepatic FMOs exhibit a developmental switch somewhat reminiscent of that seen in the CYP3A family.28 FM01 was readily observed in two laboratories in hepatic tissue during gestation (at 14-17 weeks and 8-15 weeks), whereas FM03 was undetectable. FM01 expression declined during fetal development to undetectable levels at birth and was undetectable in adult tissues. In contrast, the onset of FM03 expression was highly variable. Most neonates failed to express FM03, but expression was evident by 1-2 years of age. Intermediate FM03 expression was observed until 11 years of age, after which a gender-independent increase was seen from 11 to 18 years. Because the decline in CYP3A7 expression is accompanied by a simultaneous increase in CYP3A4/3A5, CYP3A expression is relatively invariant. On the other hand, the absence of FM01 at birth and the delayed onset of FM03 result in a null hepatic FMO phenotype in the neonate. The developmental picture is not yet complete, however, because there is no information on the developmental expression of FMOs in extrahepatic tissues.
With respect to the ontogeny of Phase I enzymes in elderly persons, the bulk of evidence has not suggested any definitive relationship between age and change in hepatic microsomal protein content or activities of various cytochrome P450 enzymes including the common variants of CYP2D6.11 Two laboratories observed an age-related decline in CYP3A and 2E1, but not in CYP1A2 or 2C; there were, however, also confounding factors including disease, drugs, and smoking that render these findings moot.10
Several decades have elapsed since the perinatal inefficiencies of glucuronida-tion and acetylation in infants were identified,2 but knowledge of developmental changes is still far from complete, mainly because of ethical and technical difficulties that retard or prevent their systematic investigation. Nevertheless, there are indications that many drug-metabolizing enzymes are expressed early in development. For example, there is evidence for glutathione-S-transferases (GSTs) in fetal liver, lung, and kidney, for NAT1 in fetal tissues, for some isoforms of glucuronosyltranferases and sulfotransferases in fetal liver and other tissues, and for epoxide hydrolases 1 and 2 in fetal liver. However, nothing is known about human NAT2 developmental expression, the more important isoform of NAT to drug and toxicant metabolism in adults.32
Whether impairment of Phase I enzymes is associated with aging has, for some time, been a controversial issue. In their review of the literature, Le Couteur and McLean found no relationship between age and either the hepatic content or activity of various cytochrome P450 enzymes,33 but by analyzing the results of published studies into in vivo clearance of drugs, they concluded that the effect of aging on hepatic drug metabolism was likely to be secondary to the reduction of blood flow and liver size, as stated in the following section.
With respect to the effects of aging on Phase II enzymes, data on human subjects are even more limited and spotty than for Phase I enzymes. One study found no change in paracetamol glucuronidation or sulfation in aging human liver preparations.10
Recently, three drug-metabolizing enzyme polymorphisms were examined to detect a relationship between them and longevity, but none was found.34 The distribution of genotypes for CYP2D6, and two conjugating enzymes, NAT2 and GSTM1, but none of the phenotypes for CYP2D6 extensive or poor meta-bolizers, rapid or slow acetylators, and active or defective GSTM1 correlated with human longevity, alone or in combination. The expression or activity of drug transporters in liver, or of P-glycoprotein and multidrug resistance-associated protein, is of recent interest in drug clearance, but as yet no data are available that describe the effects of age on them.10
Bodily clearance of therapeutic drugs and other substrates is a function of both metabolic capacity and blood flow, and in some cases blood protein binding.10,35 To interpret kinetic data at different stages of development and aging, it is important to distinguish between ''high extraction'' and ''low extraction'' drugs. The metabolic clearance of highly extracted drugs is primarily determined by hepatic blood flow, and is termed ''flow-limited metabolism''; in contrast, the metabolic clearance of poorly extracted drugs is influenced mainly by intrinsic clearance (i.e., by the metabolizing capacity) of hepatic tissue, and is termed ''capacity limited.''
Studies in Infants and Children A number of drugs that are substrates for Phase I metabolism have been classified as having high or low hepatic extraction from adult human pharmacokinetic data (Table 4.2). Antiepileptics and certain benzodiazepines that are frequently used therapeutically in infants are low extraction drugs. The half-life of these drugs depends primarily on drug-metabolizing activity and can serve as an approximate estimate of the capacity to metabolize the drug. Aminophylline and caffeine both have lengthy plasma half-lives compared to those in adults and both are substrates for CYP1A, which is consistent with the extremely low activity of CYP1A in fetal liver. On the other hand, the capacity to metabolize carbamazepine and phenytoin in newborns is well developed at birth. Carbamazepine is a substrate of CYP3A4/5 while phenytoin is a substrate of CYP2C9. Perhaps the enhanced capacity to metabolize these substrates in newborns is a result of intrauterine induction. The fact that the maximum velocity (Vmax) for oxidation of phenytoin in children exceeds that in adults explains the recommendation of higher doses in children than adults.35
The half-life of drugs belonging to the high extraction group depends largely on hepatic blood flow, and only to a minor extent on metabolic capacity. All of the examples cited in Table 4.2 have longer elimination times after an intravenous dose in newborns than adults, but the drugs in this group are less commonly used in infants than adults.
Some drugs not classified with respect to hepatic clearance are also included in Table 4.2. Among these, the overall impression is that drug elimination in neonates is slower than in adults. Not only is there variation from drug to drug, but also from newborns to adults. This suggests that attempts to predict drug metabolic capacity for children from adult data would likely be unsuccessful.
The half-lives suggest that the metabolism of most drugs is reduced in the neonatal period, but many drugs do not conform to this trend. For certain drugs, alternative metabolic pathways may be quantitatively more significant during early life than later on, as acetaminophen, salicylic acid, and theophylline il-lustrate.35 In the full-term neonate, acetaminophen and salicylic acid are eliminated primarily as the sulfate and glycine conjugates, respectively, while adults eliminate both drugs primarily as glucuronide conjugates. Theophylline, in contrast, is eliminated by premature and full-term neonates mainly by direct
Table 4.2 Half-Lives of Drugs with Low or High Hepatic Extraction and Drugs Unclassified with Respect to Hepatic Extraction35
Drugs with low hepatic clearance
Drugs with high hepatic clearance
Drugs unclassified with respect to hepatic extraction
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