Background. The 3A subfamily of cytochrome P450 (CYP3A) accomplishes phase I metabolism for approximately half of the available medications. We aimed to review the recent advances in our understanding of CYP3A activity, which could apply to infants and toddlers.
Material and Methods. A literature review.
Results. The reviewed recent data cover: CYP3A7 expression and functions, changes of CYP3A4 function in the first two years of life, CYP3A intestinal metabolism and zonation, CYP3A metabolic programming, pediatric CYP3A pharmacogenetics, the impact of critical illness on CYP3A, phenotyping, and other clinical implications of a better comprehension of CYP3A biology.
Conclusions. Although the knowledge of CYP3A enzymes has already changed pediatric practice, much more is to be expected in the upcoming years. The areas to watch include: endogenous markers for phenotyping, new CYP3A7 substrates and products, pharmacogenetic interactions with transporter genes for non‑immunomodulatory drugs, as well as interactions with microbiota and specific bioactive foodstuffs.
- Strougo A, Yassen A, Monnereau C, Danhof M, Freijer J. Predicting the „First dose in children” of CYP3A‑metabolized drugs: Evaluation of scaling approaches and insights into the CYP3A7-CYP3A4 switch at young ages. J Clin Pharmacol. 2014;54:1006–15.
- Meier R, Bi C, Gaedigk R, Heruth DP, Ye SQ, Leeder JS, et al. Ontogeny‑related pharmacogene changes in the pediatric liver transcriptome. Pharmacogenet Genomics. 2018;28:86–94.
- Creemer OJ, Ansari‑Pour N, Ekong R, Tarekegn A, Plaster C, Bains RK, et al. Contrasting exome constancy and regulatory region variation in the gene encoding CYP3A4: an examination of the extent and potential implications. Pharmacogenet Genomics. 2016;26:255–70.
- Beaumont RN, Warrington NM, Cavadino A, Tyrrell J, Nodzenski M, Horikoshi M, et al. Genome‑wide association study of offspring birth weight in 86 577 women identifies five novel loci and highlights maternal genetic effects that are independent of fetal genetics. Hum Mol Genet. 2018;27:742–56.
- Emoto C, Fukuda T, Johnson TN, Adams DM, Vinks AA. Development of a Pediatric Physiologically Based Pharmacokinetic Model for Sirolimus: Applying Principles of Growth and Maturation in Neonates and Infants. CPT Pharmacomet Syst Pharmacol. 2015;4:e17.
- Salem F, Johnson TN, Abduljalil K, Tucker GT, Rostami‑Hodjegan A. A re‑evaluation and validation of ontogeny functions for cytochrome P450 1A2 and 3A4 based on in vivo data. Clin Pharmacokinet. 2014;53:625–36.
- Pacifici GM. Clinical pharmacology of fentanyl in preterm infants. A review. Pediatr Neonatol. 2015;56:143–8.
- Johnson TN, Jamei M, Rowland‑Yeo K. How Does In Vivo Biliary Elimination of Drugs Change with Age? Evidence from In Vitro and Clinical Data Using a Systems Pharmacology Approach. Drug Metab Dispos Biol Fate Chem. 2016;44:1090–8.
- Emoto C, Fukuda T, Mizuno T, Schniedewind B, Christians U, Adams DM, et al. Characterizing the Developmental Trajectory of Sirolimus Clearance in Neonates and Infants. CPT Pharmacomet Syst Pharmacol. 2016;5:411–7.
- Brussee JM, Yu H, Krekels EHJ, de Roos B, Brill MJE, van den Anker JN, et al. First‑Pass CYP3A‑Mediated Metabolism of Midazolam in the Gut Wall and Liver in Preterm Neonates. CPT Pharmacomet Syst Pharmacol. 2018.
- Kitaoka S, Hatogai J, Ochiai W, Sugiyama K. Zonation of the drug‑metabolizing enzyme cytochrome P450 3A in infant mice begins in pre‑weaning period. J Toxicol Sci. 2018;43:223–7.
- Tien Y‑C, Liu K, Pope C, Wang P, Ma X, Zhong X. Dose of Phenobarbital and Age of Treatment at Early Life are Two Key Factors for the Persistent Induction of Cytochrome P450 Enzymes in Adult Mouse Liver. Drug Metab Dispos. 2015;43:1938–45.
- Ni S‑Q, Lou Y, Wang X‑M, Shen Z, Wang J, Zhao Z‑Y, et al. A high‑fat high‑energy diet influences hepatic CYP3A expression and activity in low‑birth‑weight developing female rats. World J Pediatr. 2016;12:489–97.
- Zhu Z‑W, Ni S‑Q, Wang X‑M, Wang J, Zeng S, Zhao Z‑Y. Hepatic CYP3A expression and activity in low birth weight developing female rats. World J Pediatr. 2013;9:266–72.
- Yang T‑H, Chen Y‑K, Xue F, Han L‑Z, Shen C‑H, Zhou T, et al. Influence of CYP3A5 genotypes on tacrolimus dose requirement: age and its pharmacological interaction with ABCB1 genetics in the Chinese paediatric liver transplantation. Int J Clin Pract Suppl. 2015;53–62.
- Uesugi M, Kikuchi M, Shinke H, Omura T, Yonezawa A, Matsubara K, et al. Impact of cytochrome P450 3A5 polymorphism in graft livers on the frequency of acute cellular rejection in living‑donor liver transplantation. Pharmacogenet Genomics. 2014;24:356–66.
- Madsen MJ, Bergmann TK, Brøsen K, Thiesson HC. The Pharmacogenetics of Tacrolimus in Corticosteroid‑Sparse Pediatric and Adult Kidney Transplant Recipients. Drugs RD. 2017;17:279–86.
- López‑García MA, Feria‑Romero IA, Serrano H, Rayo‑Mares D, Fagiolino P, Vázquez M, et al. Influence of genetic variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A4 on antiepileptic drug metabolism in pediatric patients with refractory epilepsy. Pharmacol Rep. 2017;69:504–11.
- Llop S, Tran V, Ballester F, Barbone F, Sofianou‑Katsoulis A, Sunyer J, et al. CYP3A genes and the association between prenatal methylmercury exposure and neurodevelopment. Environ Int. 2017;105:34–42.
- Vet NJ, Brussee JM, de Hoog M, Mooij MG, Verlaat CWM, Jerchel IS, et al. Inflammation and Organ Failure Severely Affect Midazolam Clearance in Critically Ill Children. Am J Respir Crit Care Med. 2016;194:58–66.
- Ince I, de Wildt SN, Peeters MYM, Murry DJ, Tibboel D, Danhof M, et al. Critical illness is a major determinant of midazolam clearance in children aged 1 month to 17 years. Ther Drug Monit. 2012;34:381–9.
- Hohmann N, Haefeli WE, Mikus G. CYP3A activity: towards dose adaptation to the individual. Expert Opin Drug Metab Toxicol. 2016;12:479–97.
- Aubry A‑F, Dean B, Diczfalusy U, Goodenough A, Iffland A, McLeod J, et al. Recommendations on the Development of a Bioanalytical Assay for 4β‑Hydroxycholesterol, an Emerging Endogenous Biomarker of CYP3A Activity. AAPS J. 2016;18:1056–66.
- Doggrell SA, Hancox JC. Cardiac safety concerns for domperidone, an antiemetic and prokinetic, and galactogogue medicine. Expert Opin Drug Saf. 2014;13:131–8.
- Bernard E, Mialou V, Dony A, Garnier N, Renard C, Bleyzac N. [Lacidipine efficacy and safety for high blood pressure treatment in pediatric oncohematology]. Arch Pediatr Organe Off Soc Francaise Pediatr. 2014;21:1101–5.
- Cotton RB, Shah LP, Poole SD, Ehinger NJ, Brown N, Shelton EL, et al. Cimetidine‑associated patent ductus arteriosus is mediated via a cytochrome P450 mechanism independent of H2 receptor antagonism. J Mol Cell Cardiol. 2013;59:86–94.
- Stiehl SR, Squires JE, Bucuvalas JC, Hemmelgarn TS. Tacrolimus interaction with dexmedetomidine--a case report. Pediatr Transplant. 2016;20:155–7.
- Moultrie H, McIlleron H, Sawry S, Kellermann T, Wiesner L, Kindra G, et al. Pharmacokinetics and safety of rifabutin in young HIV‑infected children receiving rifabutin and lopinavir/ritonavir. J Antimicrob Chemother. 2015;70:543–9.
- Hawkes CP, Li D, Hakonarson H, Meyers KE, Thummel KE, Levine MA. CYP3A4 Induction by Rifampin: An Alternative Pathway for Vitamin D Inactivation in Patients With CYP24A1 Mutations. J Clin Endocrinol Metab. 2017;102:1440–6.