New perspectives on the impact of cytochrome P450 3A expression for pediatric pharmacology.
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.
Stevens
Jeffrey C
JC
Pfizer Global Research and Development, 800 N. Lindbergh Blvd, Creve Coeur, MO 63167, USA. jeffrey.c.stevens@pfizer.com
D000367:Age Factors; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008099:Liver / Q000201:enzymology*; D008874:Midazolam / Q000378:metabolism; D010372:Pediatrics; D010600:Pharmacology
D014151:Anti-Anxiety Agents; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C510164:CYP3A5 protein, human; C103123:CYP3A7 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam