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Invited Review

Intestinal Metabolism and Transport of Drugs in Children: The Effects of Age and Disease

Johnson, Trevor N*; Thomson, Mike

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Journal of Pediatric Gastroenterology and Nutrition: July 2008 - Volume 47 - Issue 1 - p 3-10
doi: 10.1097/MPG.0b013e31816a8cca
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Abstract

From birth onward, changes in the pharmacokinetics and pharmacodynamics of administered drugs occur as a consequence of a whole host of factors, including changes in body composition, maturation of organs and enzymes, nutrition, genetics, and changes in drug receptors. Accordingly, effective and safe drug therapy in neonates, infants, children, and adolescents requires a thorough understanding of human ontogeny and the processes that govern the absorption, distribution, metabolism, excretion, and action of drugs (1).

DRUG METABOLISM

The liver is the major site of drug metabolism, the process of which is normally divided into phase 1 reactions, where a reactive chemical group is added, either so the metabolite is excreted or, more commonly, as a precursor to phase 2 reactions. Phase 2 reactions include glucuronidation, sulphation, methylation, acetylation, and glutathione conjugation, resulting in products that are generally water soluble and easily excreted.

The most important group of phase 1 enzymes is the cytochrome P450 enzyme (CYP), catalyzing the mixed function oxidation of drugs and other xenobiotics. The CYP isozymes are a superfamily of enzymes, of which the most important human isoforms are CYP1A2, 2A6, 2B6, 2C8–10, 2C19, 2D6, 2E1, and 3A4 and 5 (2). Members of the CYP3A subfamily are the most abundant and important, being involved in the metabolism of approximately 50% of all drugs. CYP3A4 is the most abundant member of the CYP3A family; CYP3A5 is polymorphically expressed in approximately 17% of the white population (3).

DEVELOPMENTAL EXPRESSION OF CYP ENZYMES IN HUMAN LIVER

In Vitro Studies

Several studies have investigated the development of hepatic CYP enzymes with age. In general, the fractional expression of each enzyme with age, in comparison with adult population, follows a hyperbolic pattern (4).

The development of the CYP3A family is unusual in that CYP3A4/5 activity as assessed in vitro increases from birth to 1 year, together with a corresponding decrease in CYP3A7, the main fetal form of cytochrome P450 (5). The in vitro development of hepatic phase 1 and phase 2 drug-metabolizing enzymes has been extensively reviewed (6,7). Reduced expression of CYP enzymes is one of several factors that will lead to the altered hepatic clearance of drugs in neonates, infants, and children. Other factors include changes in liver size, liver blood flow, and protein binding.

In Vivo Studies

In general, the rates at which drugs are cleared by hepatic drug metabolism in humans seem to be reduced especially during the first month of life because of reduced enzyme expression (eg, midazolam [MDZ], a CYP3A4 substrate in preterm infants) (8). Metabolic clearance then increases to a maximum between 2 and 10 years of age, followed by a steady decline into adulthood (9). The higher systemic weight normalized clearance in children compared with adults is thought to be due to increased liver size relative to body size.

Presence of Drug-Metabolizing Enzymes and Drug Transporters in the Small Bowel

In addition to the liver, the CYP enzymes are also expressed within the enterocytes of the small intestinal mucosa (10). As a consequence, the potential exists for substantial presystemic metabolism and thus reduced bioavailability as the drug passes through the small intestine and liver. CYP enzymes are located at the villous tip just beneath the brush border at the apex of the enterocyte (Fig. 1A) (11).

FIG. 1
FIG. 1:
Cross-sections (original magnification ×200) of human duodenum immunostained by use of a polyclonal goat anti-rat CYP3A2 antibody, which fully cross-reacts with human CYP3A, showing the presence of CYP3A in the brush border enterocytes (brown hematoxylin staining). Staining intensity decreases from the villous tip down into the crypt cells. A = healthy tissue; B = on diagnosis of celiac disease. (From Johnson TN et al.Br J Clin Pharmacol 2001;51:45160, with permission from Blackwell Publishing.)

Expression decreases distally from duodenum to ileum with 75% of CYP3A in the duodenum and jejunum (12). On average, CYP3A4/5 and 2C9 account for 80% and 15%, respectively, of the total immunoquantifiable CYP enzymes in the human small intestine. Others include CYPs 1A1/2, 2C19, 2J2, and 2D6 (13). Little correlation exists between hepatic and intestinal CYP3A4 activities within individuals, which suggests independent regulation at the 2 sites. Considerable interpatient heterogeneity exists in the expression of the CYP3A subfamily in human small bowel, and this is likely to contribute to the variable kinetics of orally administered drug substrates. Concordant with liver, enterocytic CYP3A5 is also polymorphically expressed in approximately 20% to 70% of adults, depending on ethnicity (14).

Although the total mass of CYP3A in the entire small intestine has been estimated to be approximately 1% of that in the liver (12), human studies have demonstrated that enterocytic CYP3A can make a significant contribution, in some cases equal to that of the hepatic enzyme, to the overall metabolism of several drugs, including cyclosporin (15) and MDZ (16). These substrates are absorbed by the transcellular route and therefore pass through the enterocyte and the strategically expressed CYP3A enzyme. Therefore, it is the positioning of the enzyme, rather than total quantity, that is important in the intestinal first pass of these and other drugs.

P-glycoprotein (P-gp) is an adenosine triphosphate–dependent efflux transporter protein that is constitutively expressed in normal tissues, including the gastrointestinal tract, liver, brain, and placenta. The presence of high levels of P-gp in the villous tips on the apical side of small bowel enterocytes, along with CYP3A4, has been identified as a concerted defense mechanism limiting the oral bioavailability of drugs, dietary mycotoxins, and other xenobiotics (17). P-gp and CYP3A4 share many of the same substrates (18); 3 mechanisms have been suggested (19) to explain how P-gp may limit oral drug bioavailability (Fig. 2):

FIG. 2
FIG. 2:
Potential functional relation between enterocyte P-gp and CYP3A4. Clumen = concentration of drug in intestinal lumen; Cent = concentration of drug in the enterocyte; Cmet = concentration of metabolite; Qent = blood flow to enterocyte. Yellow arrows represent passive diffusion of drug and metabolite; green arrows represent active transport by P-gp.
  • Preventing parent drug diffusion across the apical brush border membrane
  • Prolonging the duration of absorption (increasing the extent of exposure of the drug to enterocyte CYP3A4)
  • Selectively removing metabolites from within the enterocyte, preventing product inhibition of primary drug metabolism

CLINICAL CONSEQUENCES OF INTESTINAL CYP3A4 AND PGP: SOME KEY EXAMPLES OF EFFECTS ON DRUG DISPOSITION

Cyclosporin

Cyclosporin is a widely used immunosuppressant drug that has an average bioavailability of approximately 30% (range 5%–89%) for the conventional formulation. Initially this was thought to be due to the unfavorable physicochemical characteristics of cyclosporin, which is highly lipid soluble and therefore poorly water soluble. However, research evidence soon pointed to the effects of intestinal metabolism and P-gp in reducing cyclosporin bioavailability.

When cyclosporin was instilled into the small bowel of liver transplant patients during the anhepatic phase of a liver transplant operation, metabolites could be measured in the plasma because of intestinal metabolism (15). This finding was confirmed by a study using microsomes prepared from different segments of the small intestine, with the metabolism of cyclosporin occurring predominantly in microsomes from the duodenum, the area of highest CYP3A expression (20).

The concomitant administration of ketoconazole decreases intravenous cyclosporin clearance and increases oral cyclosporin bioavailability because of the inhibition of hepatic and enterocytic CYP3A enzymes, respectively (21). Grapefruit juice is a selective inhibitor of intestinal CYP3A4 with little effect on P-gp and has been shown to increase cyclosporin bioavailability by decreasing gut wall metabolism (22).

Lown et al (23) showed that the extent of intestinal metabolism of cyclosporin did not depend entirely on the level of intestinal CYP3A4 but that P-gp seemed to be the rate-limiting step in intestinal cyclosporin metabolism/absorption. In liver transplant recipients treated with cyclosporin, higher P-pg protein expression correlated with poor survival (24).

Midazolam

Midazolam is a sedative/hypnotic drug metabolized by CYP3A4 to both 1- and 4-hydroxymidazolam. Intravenous midazolam is a useful probe substrate for hepatic CYP3A4 activity.

As with cyclosporin, when intraduodenal MDZ was administered to 5 liver transplant patients during the anhepatic phase of surgery, 43% of the parent drug was observed to be metabolized on transit through the intestinal mucosa (16). However, unlike cyclosporin, which has low solubility and high permeability, MDZ has high solubility and high permeability and, although transported by P-gp, will cross biological membranes quickly; thus, transporter effects on drug disposition will be minimal (25). The high metabolic capacity of the proximal small bowel was confirmed by a pharmacokinetic study comparing intravenous and oral MDZ administration in a crossover study involving 20 patients. The extraction ratios for the gut and liver were found to be 43% and 44%, respectively, giving an overall bioavailability of 30% (26). The rate of formation of 1-hydroxymidazolam was observed to be highest in microsomes prepared from the jejunum than in those from more distal sections of the small bowel.

In an in vivo study of intravenous and oral MDZ, ketoconazole has been shown to inhibit CYP3A activity to a greater extent in the intestine than in the liver, presumably because of the higher concentrations of the inhibitor in the small bowel (27). Grapefruit juice has been shown to inhibit small bowel metabolism of MDZ (28).

INTESTINAL CYP ENZYMES AS A PROTECTIVE BARRIER TO INGESTED TOXINS

The presence of CYP enzymes within the small bowel may act as a protective mechanism against ingested toxins. Profound increases in intestinal CYP1A1 expression were recorded in healthy human volunteers on exposure to a dietary loading of heterocyclic amines and polycyclic aromatic hydrocarbons (29). Patients with high intestinal CYP1A1 protein had lower detectable polycyclic aromatic hydrocarbon DNA adduct levels in their blood.

DEVELOPMENTAL EXPRESSION OF DRUG-METABOLIZING ENZYMES AND DRUG TRANSPORTERS IN THE GASTROINTESTINAL TRACT IN CHILDREN

Until recently, relatively little was known about the development of CYP enzymes and drug transporters in the gastrointestinal tract in children. Significant differences have been shown in the expression and activity of intestinal forms of CYP3A in the rat as a function of age. Intestinal CYP3A showed a marked surge at weaning, which may be a protective mechanism against ingested toxins (30). The rat, however, is a poor model for human CYP3A development in the intestine because of differences in the development of the intestine itself and enzyme differences between the 2 species. From that study, the same research group investigated the effects of age and disease on the expression and activity of CYP3A4 in a pediatric population (31). Duodenal biopsy specimens and surgical sections were collected from 104 pediatric patients age 2 weeks to 17 years and also from 11 fetuses. CYP3A4 expression was assessed by Western blotting and immunohistochemistry, and activity was measured by the rate of formation of 6β-hydroxytestosterone from testosterone. Villin expression was used as a marker of enterocyte harvest to normalize CYP3A4 expression and activity data. In the 74 histologically normal biopsy specimens, there were statistically significant increases in CYP3A4 expression and activity with age (Fig. 3). CYP3A4 was practically absent in the fetal duodenum and was expressed at relatively low levels in the neonate.

FIG. 3
FIG. 3:
Age-related changes in the villin corrected expression (A) and activity (B) of CYP3A4 in histologically normal duodenal sections. The numbers in each group are given in brackets. Error bars are ±SD. A, For CYP3A protein expression measured by Western blotting, statistically significant differences (P < 0.05) were observed between the fetus group and all of the other groups and between neonates and children older than 5 years. B, CYP3A activity measured by the rate of 6β hydroxytestosterone (6OHT) formation from testosterone; a statistically significant difference (P < 0.05) was observed only between neonates and children older than 12 years. (From Johnson TN et al. Br J Clin Pharmacol 2001;51:45160, with permission from Blackwell Publishing.)

Two further studies have investigated the development of CYP3A4/5 by measuring mRNA. One of these studies (32) showed increased CYP3A4 mRNA levels (approximately 2-fold) in the neonate compared with the fetus; in turn, young adults had approximately 4- to 5-fold the mRNA levels compared with neonates. By contrast, Fakhoury et al (33) showed a decrease in CYP3A4 and CYP3A5 mRNA in children 1 to 6 years old compared with children 1 month to 1 year old and, in turn, reduced mRNA expression in children over 6 years old compared with those 1 to 6 years old. They suggest that posttranscriptional regulatory mechanisms may be involved in the expression of the actual CYP3A enzyme. Although there is evidence that a change to formula feeding from breast milk accelerates the development of CYP1A2 and CYP3A4 in the infant liver, no equivalent studies, to our knowledge, have been completed on the effects of nutritional changes on intestinal CYP enzymes (34).

In humans, P-gp mRNA and protein were detected as early as 11 to 14 weeks' gestation in the liver and kidney but were detected only in the intestines of term babies (35). Miki et al (32) demonstrated slightly higher expression of intestinal MDR1 (the gene coding for P-gp expression) in neonates than in fetuses and then a large increase (approximately 4-fold) in expression between young adults and neonates. Clearly, postconceptional age–related maturation of these transporters is implied by these findings. Fakhoury et al (33) detected significant levels of P-gp mRNA in the small intestine across the pediatric age range but did not show a specific developmental pattern.

POTENTIAL CLINICAL CONSEQUENCES FOR MEDICINES USED IN CHILDREN

Many oral drugs used in pediatric clinical practice are major substrates for CYP3A. An estimate taken from the Lexi-Comp Pediatric Dosage Handbook International(36) suggests the number to be approximately 180 drugs. However, according to the biopharmaceutics classification system (37), only those drugs in class 1 or 2 (high-permeability drugs whose predominant route of clearance is metabolism), which includes approximately 30, or 17%, of these drugs, are likely to be significant substrates for intestinal metabolism and/or transporters. Clearly, for these drugs this added first-pass effect may be of some clinical significance in day-to-day practice. Some drugs used in pediatrics may have variable bioavailability because of alteration in small bowel enzyme and transporter systems (Table 1) (38).

TABLE 1
TABLE 1:
Selected drugs used in children with low and variable oral bioavailability believed to be due in part to intestinal first-pass metabolism(38)

The effects of intestinal CYP3A and P-gp as previously described in adults will also have significant effects on the pharmacokinetics of drugs administered to children, with an added level of complexity because of their developmental expression and activity. In theory, the reduced expression of CYP3A (and possibly P-gp) in neonates and young children may result in the increased bioavailability of drugs such as oral MDZ and cyclosporin in these age groups. However, these effects may have to be offset against other factors that may reduce bioavailability because of the effects on absorption, such as altered gut physiology, intraluminal pH, reduced gastric emptying, and intestinal transit time. Very few studies have allowed the clinical consequences of intestinal metabolism/transport to be assessed in the pediatric group, but these are desirable.

The oral bioavailability (F) of cyclosporin has been shown to be independent of age in a pediatric population 1.1 to 16.8 years old. The median value for F was 20.6%, which is within range of the findings in adult studies (20%–30%). The authors concluded that poor bioavailability was due to poor absorption and prehepatic metabolism of cyclosporin (39). The F of cyclosporin in pediatric heart and kidney transplant patients was similar to the values in adults, whereas the F in pediatric liver transplant patients was lower than in other populations (40), possibly because of the surgical procedure and reduced effective bowel length. Brunner et al (41) studied 6 pediatric patients 7 to 17 years old and demonstrated that the coadministration of an oral solution of cyclosporin with grapefruit juice increased the overall exposure to the drug by 1.5-fold. Fanta et al (42) studied the effects of age on the pharmacokinetics of cyclosporin in 162 pretransplant children 0.36 to 17.5 years old and speculated that the fraction of the first-pass metabolism of cyclosporin occurring in the small intestine by the interplay of CYP3A4 and P-glycoprotein is constant with age. Although pediatric studies with cyclosporin demonstrate that intestinal metabolism occurs in children, they provide no information on the extent of intestinal metabolism with age.

Tacrolimus, another calcineurin inhibitor, is also metabolized by intestinal CYP3A4/CYP3A5 and transported by P-gp. Masuda et al (43) presented data on 2 pediatric small bowel transplant recipients (3 years 6 months old and 6 years 10 months old) in whom they investigated the time course of MDR1 (coding for P-gp) and CYP3A4 mRNAs after transplant. They showed that tacrolimus dose was strongly correlated with MDR1 mRNA but not CYP3A4 mRNA. They conclude that monitoring the reduction in expression of MDR1 mRNA in the graft intestine may be useful in determining when to change from intravenous to oral drug after transplant.

A study on oral MDZ in preterm infants (44) showed a higher bioavailability of 49%, compared with 27% to 36% in children. This observation could be explained by the reduced intestinal and hepatic first-pass metabolism of MDZ in the neonate. In an unpublished study in 8 children 3 to 10 years old who received oral MDZ for sedation before endoscopy and duodenal biopsy, both the MDZ plasma concentrations and the in vitro intestinal CYP3A4 activity were measured close together in time. MDZ is metabolized to 1-hydroxymidazolam (1-OHMDZ), and the 1-OHMDZ:MDZ ratio is a marker of in vivo CYP3A activity (both intestinal and liver after oral administration). Although it was not statistically significant, there was a correlation between intestinal CYP3A activity and the 1-OHMDZ:MDZ ratio (Fig. 4), with the intestinal CYP3A activity accounting for more than 30% of the variability in the ratio, thus suggesting that the developmental expression of intestinal CYP3A will influence drug pharmacokinetics.

FIG. 4
FIG. 4:
Relation between the activity of in vitro duodenal CYP3A4 measured in pediatric biopsy samples and the in vivo 1-hydroxymidazolam; midazolam metabolite ratio measured in the same children. Midazolam was administered orally to the patient at a dosage of 0.5 mg/kg for preoperative sedation before the procedure, and a blood sample was taken early in the procedure. This metabolite ratio is a recognized measure of in vivo CYP3A activity both in the small bowel and in the liver, with samples taken early (first sample) being more reflective of intestinal CYP3A activity. (From Johnson TN. Developmental and Pathological Changes in Intestinal Cytochrome P450 3A. PhD thesis, University of Sheffield, UK, 2001.)

Budesonide has an extensive first-pass metabolism by CYP3A4 in the duodenum and jejunum and also in the liver. Systemic exposure and availability after oral administration of the 9-mg enteric-coated capsules were evaluated in 8 children 9 to 14 years old and in 6 adults with mild to moderate Crohn disease. Overall, there was no significant difference in bioavailability between the 2 groups (45). This is not unexpected, inasmuch as the expression of CYP3A4 in both the liver and the intestine is likely to be close to adult values in the pediatric age range studied.

ASSOCIATION BETWEEN GASTROINTESTINAL DISEASE AND INTESTINAL CYP EXPRESSION AND ACTIVITY

Celiac disease, or gluten-sensitive enteropathy, is characterized by villous atrophy in the proximal small bowel. The decreased expression of CYP3A in untreated celiac disease (Fig. 1B) and its return to normal in people receiving a gluten-free diet has been shown in adults (46). In a study of 9 pediatric patients with celiac disease (31), 3 boys and 6 girls, median age 5.5 years (range 1–16 years), biopsies were performed at the time of diagnosis, after a gluten-free diet, and in 6 patients after gluten rechallenge. The results of this study are shown in Fig. 5. Intestinal CYP3A expression was reduced in active celiac disease, came back to normal levels after consumption of a gluten-free diet, and again was reduced with consumption of a gluten-containing diet.

FIG. 5
FIG. 5:
Mean immunohistochemical staining scores (staining score is the visible amount of brown staining related to CYP3A4 within the enterocytes on a scale of 0–4) for duodenal CYP3A expression in 9 patients on diagnosis of celiac disease and after gluten-free diet and for 6 patients after gluten rechallenge. Each point is the mean score from 3 experiments, each scored by 3 observers.

The decreased enterocytic CYP3A4 activity in celiac disease may have clinical implications. In treated, well-controlled disease, the effects are probably minimal. However, in a proportion of individuals, the disease will remain either undiagnosed or poorly controlled, and hence the patients will be at increased risk of systemic exposure to dietary mycotoxins and toxic effects from the increased bioavailability of some drugs. So-called refractory celiac disease may also have an implication here, although it is likely that this situation is due more to noncompliance with diet than to any other factor.

Enterocytic CYP1A enzymes will also be lost in active celiac disease, thus increasing systemic exposure to some carcinogens. In addition to reducing the systemic bioavailability of toxins, the intestinal CYP enzymes may also act as a clearing system within the gastrointestinal tract, thereby preventing or diminishing their passage to the colon (47). The increased systemic and local exposure to toxins and carcinogens may, in part, account for the increased incidence of intestinal lymphomas and adenocarcinomas found in celiac disease, although this remains conjectural. (48)

A study by Maezono et al (49) reported 2 cases of pediatric living-related liver transplant recipients (1 year 8 months old and 2 years 4 months old) who both showed increases in blood concentrations of cyclosporin and tacrolimus during a diarrheal episode. The authors investigated the effects of intestinal inflammation on intestinal CYP3A4 and P-gp activity using an endotoxin-induced intestinal damage model and observed reduced activity in both. Thus, elevated cyclosporin and tacrolimus blood concentrations during enteritis-induced diarrhea may be partly due to reduced intestinal CYP3A4 and P-gp activity.

Klotz et al (50) studied 25 patients with Crohn disease and 37 with ulcerative colitis. In both groups, the expression of CYP1A1 in the terminal ileum, colon, sigmoid, and rectum was 2-fold higher than in a control group. This suggests that this enzyme may have a role in the etiology or pathogenesis of inflammation in these disorders. Alternatively, the higher expression of CYP1A enzymes could be a secondary effect because of the presence of xenobiotics that lead to inflammation.

The C3435T polymorphism of the MDR1 gene coding for P-gp is associated with lower intestinal P-gp expression and has been linked to the development of ulcerative colitis (51). This corroborates with previous research showing that in mdr1a knockout mice, a form of colitis develops that is similar to ulcerative colitis. This colitis can be prevented by antibiotics, which indicates a barrier function for P-gp against the invasion of bacteria or toxins (52,53). The role of P-gp in gastrointestinal disease has recently been reviewed (54).

OTHER DISEASE PROCESSES WITH POTENTIAL CLINICAL EFFECT IN TERMS OF SMALL INTESTINAL CYP EXPRESSION

With this knowledge in mind, it is interesting and important to consider which pediatric small bowel conditions could compromise or augment drug bioavailability.

These may fall into several major categories, as follows:

  • Conditions that compromise small bowel surface area and result in loss of enterocytes (eg, celiac disease; allergic enteropathy; giardial enteropathy)
  • Conditions that decrease overall small bowel surface area (eg, short bowel syndromes: congenital, autoimmune enteropathy, or postsurgical; fistulizing disease); this may be especially important when a large section of the proximal small bowel containing the majority of CYP enzymes is lost
  • Conditions that compromise small bowel motility (eg, inflammatory conditions such as pseudo-obstruction syndromes, other motility disorders)
  • Conditions that alter tight junctions and allow passage of molecules past, not through, the enterocyte (eg, inflammatory intestinal diseases, infections affecting the small bowel)
  • Conditions that affect the permeability and cell transfer of molecules (eg cystic fibrosis, tufting enteropathy, microvillous inclusion disease, other congenital enteropathies)

It is therefore clear that a large amount of clinical research, and consequent clinical impact on practice in the use of many drugs, may be implicated as a sequela of the comprehension of the importance of small intestinal drug metabolism and transport.

CONCLUSIONS

Although much progress has been made in our understanding of the development of drug elimination pathways and drug response in the pediatric population, many areas of further research remain. There is a pressing need for the generation of more data in children to provide a rational basis for dosage determination and to establish safety and efficacy in this age group. Some specific areas for further research include the following:

  • Further understanding is needed of how the underlying determinants of drug disposition change with age (eg, how the expression of the actual P-gp protein and its activity change with age; how various factors affecting drug absorption changes with age; how biliary excretion changes with age). The age-related development of a whole range of other drug transporters awaits further research.
  • Further clinical drug studies are needed to properly assess the impact of developmental changes on drug exposure in children. This is highlighted in the present review by the lack of studies to assess the clinical impact of changes in intestinal CYP3A and P-gp with age.
  • In addition to changes to the pharmacokinetics of drugs in children, further studies are also needed on changes in pharmacodynamics across the pediatric age range, especially with reference to drugs acting on the central nervous system and immune system.
  • Studies are needed on changes in drug disposition with age in relation to different diseases.

The Medicines for Children Research Network, part of a European network, has been established so that adequately powered pediatric studies can be performed on both new and existing drugs. Furthermore, European legislation along the lines of the Best Medicines for Children Act in the United States will require pharmaceutical companies to test new drugs in children with safeguards in place to prevent the performance of unnecessary studies. It is hoped that the new network and legislation will result in a much higher volume of well-conducted clinical drug studies in children.

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Keywords:

Cytochrome P450 enzymes; Intestinal drug metabolism; P-glycoprotein

© 2008 Lippincott Williams & Wilkins, Inc.