New perspectives on the impact of cytochrome P450 3A expression for pediatric pharmacology

doi:10.1016/j.drudis.2006.03.002

Drug Discovery Today

Volume 11, Issues 9–10, May 2006, Pages 440-445

https://doi.org/10.1016/j.drudis.2006.03.002 Get rights and content

Advances in the basic and clinical sciences of drug actions and safety have been applied almost exclusively to the largest demographic patient group – adults. Metabolism-dependent drug clearance is not only a primary determinant for obtaining efficacious drug exposure, but could also demonstrate clear age-dependence. These concepts are exemplified by the three major human cytochrome P450 (CYP) 3A enzymes: CYP3A4, CYP3A5 and CYP3A7. Recent preclinical and clinical studies show CYP3A7 is the most abundant CYP3A enzyme in fetal liver, with a gradual shift towards CYP3A4 expression throughout childhood. However, the polymorphic nature and regulatory intricacies of CYP3A5 and CYP3A7 expression could cause an underappreciated contribution to interindividual variability in drug response and safety.

Section snippets

General considerations of cytochrome-P450-dependent metabolism

As the primary catalyst of metabolism-based drug clearance, the P450 enzyme family has been extensively studied from structural, functional and regulatory perspectives. Although there are many P450 gene families distributed throughout the human body, gene families numbered 1, 2 and 3 provide the majority of P450s involved in therapeutic drug metabolism. In addition, these enzymes are located predominantly in the liver and intestine, and have a broad range of substrates; attributes that create a

Current understanding of CYP3A expression

One approach aimed at understanding the genetic and developmental dependence of individual CYP3A forms is considering cases where the technical advances (previously discussed) have dramatically changed or gradually reinforced certain hypotheses and conclusions relating to the regulation and function of individual CYP3A forms. For example, CYP3A4 has historically and accurately been described as the major adult-human hepatic CYP3A form, although early reports probably overestimated CYP3A4

Examples of clinical impact

Although the full spectrum of clinical studies addressing CYP3A ontogeny is beyond the scope of this review, several examples highlight the complexity of translating genotype and in vitro analyses into patient care. One of the most extensively investigated topics is the metabolic clearance of midazolam (a short-acting benzodiazepine) by neonates and children compared with adults. The plasma clearance of midazolam follows the pattern: adults > full-term neonates > pre-term neonates [57]. Given the

Conclusions and future directions

In the past five years alone, important advances have been made in understanding the contribution of genetics and development with regard to interindividual variability in drug metabolism. Although this review specifically focuses on the CYP3A subfamily, similar ontogeny analyses for other P450s and other drug-metabolizing enzyme families have recently been published (or are in progress). Because this information has coincided with the emergence of new requirements regarding pediatric drug

References (63)

H. Shirkey
Therapeutic orphans
J. Pediatr.
(1968)
J.K. Lamba
Genetic contribution to variable human CYP3A-mediated metabolism
Adv. Drug Deliv. Rev.
(2002)
T. Aoyama
Cytochrome P-450 hPCN3, a novel cytochrome P-450 IIIA gene product that is differentially expressed in adult human liver. cDNA and deduced amino acid sequence and distinct specificities of cDNA-expressed hPCN1 and hPCN3 for the metabolism of steroid hormones and cyclosporine
J. Biol. Chem.
(1989)
M.L. Schrag et al.
Covalent alteration of the CYP3A4 active site: evidence for multiple substrate binding domains
Arch. Biochem. Biophys.
(2001)
S. Ekins
In vitro and pharmacophore insights into CYP3A enzymes
Trends Pharmacol. Sci.
(2003)
T. Matsunaga
Expression and induction of CYP3As in human fetal hepatocytes
Biochem. Biophys. Res. Commun.
(2004)
O. Burk
Molecular mechanisms of polymorphic CYP3A7 expression in adult human liver and intestine
J. Biol. Chem.
(2002)
M. Kitada
P-450 HFLa, a form of cytochrome P-450 purified from human fetal livers, is the 16 alpha-hydroxylase of dehydroepiandrosterone 3-sulfate
J. Biol. Chem.
(1987)
O. Burk
The induction of cytochrome P450 3A5 (CYP3A5) in the human liver and intestine is mediated by the xenobiotic sensors pregnane X receptor (PXR) and constitutively activated receptor (CAR)
J. Biol. Chem.
(2004)
R.W. Chesney et al.
Changing requirements for evaluation of pharmacologic agents
Pediatrics
(2004)

J.S. Leeder

Pharmacogenetics and pharmacogenomics

Pediatr. Clin. North Am.

(2001)

R. Weinshilboum

Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase

Drug Metab. Dispos.

(2001)

J.F. Mineo

Recombinant humanised anti-HER2/neu antibody (Herceptin) induces cellular death of glioblastomas

Br. J. Cancer

(2004)

J.S. Ross et al.

Targeted therapy for cancer: the HER-2/neu and Herceptin story

Clin. Leadersh. Manag. Rev.

(2003)

G. Ginsberg

Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature

Toxicol. Sci.

(2002)

M.L. Christensen

Is pediatric labeling really necessary?

Pediatrics

(1999)

G.R. Wilkinson

Drug metabolism and variability among patients in drug response

N. Engl. J. Med.

(2005)

F.P. Guengerich

Cytochrome P-450 3A4: regulation and role in drug metabolism

Annu. Rev. Pharmacol. Toxicol.

(1999)

N.K. Spurr

The human cytochrome P450 CYP3 locus: assignment to chromosome 7q22-qter

Hum. Genet.

(1989)

T.L. Domanski et al.

Analysis of mammalian cytochrome P450 structure and function by site-directed mutagenesis

Curr. Drug Metab.

(2001)

S.A. Wrighton

Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3)

Mol. Pharmacol.

(1990)

J. Hakkola

Cytochrome P450 3A expression in the human fetal liver: evidence that CYP3A5 is expressed in only a limited number of fetal livers

Biol. Neonate

(2001)

P.E. Thomas

Antibodies as probes of cytochrome P450 isozymes

Adv. Exp. Med. Biol.

(1986)

T. Shimada

Characterization of microsomal cytochrome P450 enzymes involved in the oxidation of xenobiotic chemicals in human fetal liver and adult lungs

Drug Metab. Dispos.

(1996)

J.M. Hutzler et al.

Atypical kinetic profiles in drug metabolism reactions

Drug Metab. Dispos.

(2002)

M. Shou

Activation of CYP3A4: evidence for the simultaneous binding of two substrates in a cytochrome P450 active site

Biochemistry

(1994)

E.D. Kharasch

Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: noninvasive assessment by use of pupillary miosis

Clin. Pharmacol. Ther.

(2004)

E.D. Kharasch

CYP3A probes can quantitatively predict the in vivo kinetics of other CYP3A substrates and can accurately assess CYP3A induction and inhibition

Mol. Interv.

(2005)

L.Z. Benet

There are no useful CYP3A probes that quantitatively predict the in vivo kinetics of other CYP3A substrates and no expectation that one will be found

Mol. Interv.

(2005)

E.D. Kharasch

Evaluation of first-pass cytochrome P4503A (CYP3A) and P-glycoprotein activities using alfentanil and fexofenadine in combination

J. Clin. Pharmacol.

(2005)

T.D. Bjornsson

The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective

Drug Metab. Dispos.

(2003)

Cited by (58)

CYP 450 enzymes influence (R,S)-ketamine brain delivery and its antidepressant activity
2022, Neuropharmacology
Citation Excerpt :
In humans, age is one of the most important factors affecting drug metabolism capacity, especially at the extremes of life, where drug metabolism capacity seems to be significantly lowered. In infants, poor drug metabolism is caused by immaturity of several enzyme systems including CYP450 (Stevens, 2006; Stevens et al., 2008; Zanger and Schwab, 2013). The ability to clear drugs is significantly decreased in the elderly population, especially for drugs with a narrow therapeutic range, such as antipsychotics, antidepressants, anticoagulants, and beta-blockers (Zanger and Schwab, 2013).
Esketamine, the S-stereoisomer of (R,S)-ketamine was recently approved by drug agencies (FDA, EMA), as an antidepressant drug with a new mechanism of action. (R,S)-ketamine is a N-methyl-d-aspartate receptor (NMDA-R) antagonist putatively acting on GABAergic inhibitory synapses to increase excitatory synaptic glutamatergic neurotransmission. Unlike monoamine-based antidepressants, (R,S)-ketamine exhibits rapid and persistent antidepressant activity at subanesthetic doses in preclinical rodent models and in treatment-resistant depressed patients. Its major brain metabolite, (2R,6R)-hydroxynorketamine (HNK) is formed following (R,S)-ketamine metabolism by various cytochrome P450 enzymes (CYP) mainly activated in the liver depending on routes of administration [e.g., intravenous (largely used for a better bioavailability), intranasal spray, intracerebral, subcutaneous, intramuscular or oral]. Experimental or clinical studies suggest that (2R,6R)-HNK could be an antidepressant drug candidate. However, questions still remain regarding its molecular and cellular targets in the brain and its role in (R,S)-ketamine's fast-acting antidepressant effects. The purpose of the present review is: 1) to review (R,S)-ketamine pharmacokinetic properties in humans and rodents and its metabolism by CYP enzymes to form norketamine and HNK metabolites; 2) to provide a summary of preclinical strategies challenging the role of these metabolites by modifying (R,S)-ketamine metabolism, e.g., by administering a pre-treatment CYP inducers or inhibitors; 3) to analyze the influence of sex and age on CYP expression and (R,S)-ketamine metabolism. Importantly, this review describes (R,S)-ketamine pharmacodynamics and pharmacokinetics to alert clinicians about possible drug-drug interactions during a concomitant administration of (R,S)-ketamine and CYP inducers/inhibitors that could enhance or blunt, respectively, (R,S)-ketamine's therapeutic antidepressant efficacy in patients.
Neonatal cytochrome P450 CYP3A7: A comprehensive review of its role in development, disease, and xenobiotic metabolism
2019, Archives of Biochemistry and Biophysics
Citation Excerpt :
Yet, more recent studies with neonatal and pediatric livers have identified significant levels of CYP3A7 up to 24 months post-gestational age [23,26,28,29]. Unique for any known human cytochrome P450, CYP3A7 begins to gradually decrease during the third trimester of pregnancy but remains active in many individuals during the first year of life, concomitant with gradual increases in CYP3A4 beginning after birth [23,26,28,30,31]. That is, CYP3A7 and CYP3A4 appear to exhibit a mirror image pattern of expression, with CYP3A7 levels declining after birth even as CYP3A4 levels increase.
The human cytochrome P450 CYP3A7, once thought to be an enzyme exclusive to fetal livers, has more recently been identified in neonates and developing infants as old as 24 months post-gestational age. CYP3A7 has been demonstrated to metabolize two endogenous compounds that are known to be important in the growth and development of the fetus and neonate, namely dehydroepiandrosterone sulfate (DHEA-S) and all-trans retinoic acid (atRA). In addition, it is also known to metabolize a variety of drugs and xenobiotics, albeit generally to a lesser extent relative to CYP3A4/5. CYP3A7 is an important component in the development and protection of the fetal liver and additionally plays a role in certain disease states, such as cancer and adrenal hyperplasia. Ultimately, a full understanding of the expression, regulation, and metabolic properties of CYP3A7 is needed to provide neonates with appropriate individualized pharmacotherapy. This article summarizes the current state of knowledge of CYP3A7, including its discovery, distribution, alleles, RNA splicing, expression and regulation, metabolic properties, substrates, and inhibitors.
Active-site differences between substrate-free and ritonavirbound cytochrome P450 (CYP) 3A5 reveal plasticity differences between CYP3A5 and CYP3A4
2019, Journal of Biological Chemistry
Citation Excerpt :
Drug–drug interactions involving 3A enzymes can also lead to unwanted side effects during drug therapy. P450 3A4 is the most highly expressed of the 3A enzymes in adult human livers, whereas 3A7 predominates in the fetal and neonatal period (3, 4). P450 3A5 is expressed in adult human liver, as well as fetal liver, and exhibits a broader tissue distribution than 3A4 (5).
Cytochrome P450 (CYP) 3A4 is a major contributor to hepatic drug and xenobiotic metabolism in human adults. The related enzyme CYP3A5 is also expressed in adult liver and has broader age and tissue distributions. However, CYP3A5 expression is low in most Caucasians because of the prevalence of an allele that leads to an incorrectly spliced mRNA and premature termination of translation. When expressed, CYP3A5 expands metabolic capabilities and can augment CYP3A4-mediated drug metabolism, thereby reducing drug efficacy and potentially requiring dose adjustments. The extensive role of CYP3A4 in drug metabolism reflects in part the plasticity of the substrate-free enzyme to enlarge its active site and accommodate very large substrates. We have previously shown that the structure of the CYP3A5–ritonavir complex differs substantially from that of the CYP3A4–ritonavir complex. To better understand whether these differences are conserved in other CYP3A5 structures and how they relate to differential plasticity, we determined the X-ray crystallographic structure of the CYP3A5 substrate-free complex to 2.20 Å resolution. We observed that this structure exhibits a much larger active site than substrate-free CYP3A4 and displays an open substrate access channel. This reflected in part a lower trajectory of the helix F–F′ connector in CYP3A4 and more extensive π–CH interactions between phenylalanine residues forming the roof of the active-site cavity than in CYP3A5. Comparison with the CYP3A5–ritonavir complex confirmed conserved CYP3A5 structural features and indicated differences in plasticity between CYP3A4 and CYP3A5 that favor alternative ritonavir conformations.
Sedation Analgesia and Neuromuscular Blockade in Pediatric Critical Care: Overview and Current Landscape
2017, Pediatric Clinics of North America
Developmental regulation of CYP3A4 and CYP3A7 in Chinese Han population
2016, Drug Metabolism and Pharmacokinetics
CYP3A4 and CYP3A7 are generally served as the major adult and fetal liver forms, respectively, and exhibited a developmental switch during liver maturation. The objective of this study was to explore the potential mechanisms associated with the developmental switch of CYP3A4 and CYP3A7 in the Chinese Han population. We analyzed CYP3A4/7, nuclear receptors, and epigenetic modifications in human liver samples. We found that the expression levels of CYP3A4 mRNA in adults were significantly higher than the levels in fetus. In contrast, CYP3A7 mRNA expression reached a maximal level at an estimated gestational age of 25 weeks and then substantially decreased during the first year after birth. We also found that the expression level of hepatocyte nuclear factor 4 alpha (HNF4A) was most associated with CYP3A4 expression in adult liver; whereas the expression level of glucocorticoid receptor (GR) was intensively correlated with CYP3A7 expression in fetal liver. Furthermore, we illustrated the dynamic changes of H3K4me2 and H3K27me3 in the developmental switch of CYP3A7 and CYP3A4. In summary, our data suggested that HNF4A and GR, and epigenetic changes of H3K4me2 and H3K27me3 are associated with the ontogenic expressions of CYP3A4/3A7 in the livers of the Chinese Han population.
Developmental Pharmacology
2016, Smith's Anesthesia for Infants and Children, Ninth Edition

View all citing articles on Scopus

View full text

ReviewPost ScreenNew perspectives on the impact of cytochrome P450 3A expression for pediatric pharmacology

Section snippets

General considerations of cytochrome-P450-dependent metabolism

Current understanding of CYP3A expression

Examples of clinical impact

Conclusions and future directions

J. Pediatr.

Adv. Drug Deliv. Rev.

J. Biol. Chem.

Arch. Biochem. Biophys.

Trends Pharmacol. Sci.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Changing requirements for evaluation of pharmacologic agents

Pediatrics

Pharmacogenetics and pharmacogenomics

Pediatr. Clin. North Am.

Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase

Drug Metab. Dispos.

Recombinant humanised anti-HER2/neu antibody (Herceptin) induces cellular death of glioblastomas

Br. J. Cancer

Targeted therapy for cancer: the HER-2/neu and Herceptin story

Clin. Leadersh. Manag. Rev.

Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature

Toxicol. Sci.

Is pediatric labeling really necessary?

Pediatrics

Drug metabolism and variability among patients in drug response

N. Engl. J. Med.

Cytochrome P-450 3A4: regulation and role in drug metabolism

Annu. Rev. Pharmacol. Toxicol.

The human cytochrome P450 CYP3 locus: assignment to chromosome 7q22-qter

Hum. Genet.

Analysis of mammalian cytochrome P450 structure and function by site-directed mutagenesis

Curr. Drug Metab.

Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3)

Mol. Pharmacol.

Cytochrome P450 3A expression in the human fetal liver: evidence that CYP3A5 is expressed in only a limited number of fetal livers

Biol. Neonate

Antibodies as probes of cytochrome P450 isozymes

Adv. Exp. Med. Biol.

Characterization of microsomal cytochrome P450 enzymes involved in the oxidation of xenobiotic chemicals in human fetal liver and adult lungs

Drug Metab. Dispos.

Atypical kinetic profiles in drug metabolism reactions

Drug Metab. Dispos.

Activation of CYP3A4: evidence for the simultaneous binding of two substrates in a cytochrome P450 active site

Biochemistry

Intravenous and oral alfentanil as in vivo probes for hepatic and first-pass cytochrome P450 3A activity: noninvasive assessment by use of pupillary miosis

Clin. Pharmacol. Ther.

CYP3A probes can quantitatively predict the in vivo kinetics of other CYP3A substrates and can accurately assess CYP3A induction and inhibition

Mol. Interv.

There are no useful CYP3A probes that quantitatively predict the in vivo kinetics of other CYP3A substrates and no expectation that one will be found

Mol. Interv.

Evaluation of first-pass cytochrome P4503A (CYP3A) and P-glycoprotein activities using alfentanil and fexofenadine in combination

J. Clin. Pharmacol.

The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective

Drug Metab. Dispos.

Review
Post Screen
New perspectives on the impact of cytochrome P450 3A expression for pediatric pharmacology