Evidence of impaired cisapride metabolism in neonates.
OBJECTIVE
Cisapride has been shown to cause QTc prolongation in neonates in the absence of any of the known risk factors ascribed to children or adults (excessive dosage, drug-drug interactions). Our hypothesis was that the early neonatal liver may show defective elimination of cisapride resulting in its accumulation in the immature child. Owing to the difficulties associated with in vivo pharmacokinetic studies in a paediatric population, we explored the in vitro metabolism of cisapride by human cytochrome P450.


METHODS
Experiments were conducted with recombinant CYPs stably expressed in mammalian cells and with liver microsomes obtained from human foetuses, neonates, infants and adults. Cisapride metabolites were measured by high performance liquid chromatography.


RESULTS
The rate of biotransformation of cisapride was greater by recombinant CYP3A4 than by CYP3A7 (0.77 +/- 0.5 and 0.01 +/- 0.01 nmol metabolites formed in 24 h, respectively), whereas CYP1A1, 1A2, 2C8, 2C9 and 3A5 showed no activity. Norcisapride formation was significantly correlated with testosterone 6beta-hydroxylation, a CYP3A4 catalysed reaction (r = 0.71, P = 0.03) but not with the 16-hydroxylation of dehydroepiandrosterone, catalysed by CYP3A7 (r = 0.30, P = 0.29) by microsomes from a panel of livers from foetuses, neonates and infants. No or negligible cisapride metabolic activity was observed in microsomes from either foetuses or neonates aged less than 7 days, which contained mostly CYP3A7 and no CYP3A4. The metabolism of cisapride steadily increased after the first week of life in parallel with CYP3A4 activity to reach levels exceeding adult values.


CONCLUSIONS
The low content of CYP3A4 in the human neonatal liver appears to be responsible for its inability to oxidize cisapride and could explain its accumulation in plasma leading to the cases of QTc prolongation reported in this paediatric population.
Tréluyer
J M
JM
Pharmacologie Périnatale et Pédiatrique, Groupe Hospitalier Cochin-Saint Vincent de Paul (AP-HP) et Université Paris René Descartes, 82 avenue Denfert Rochereau 75674 Paris Cedex 14, France. jm.treluyer@svp.ap-hop-paris.fr
Rey
E
E
Sonnier
M
M
Pons
G
G
Cresteil
T
T
D000328:Adult; D001711:Biotransformation; D002648:Child; D002851:Chromatography, High Pressure Liquid; D020117:Cisapride / Q000378:metabolism* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005333:Fetus / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007231:Infant, Newborn; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism
D005765:Gastrointestinal Agents; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D020117:Cisapride