Metabolism and Disposition of Indomethacin in Preterm Infants

Abstract

38 preterm infants with symptomatic patent ductus arteriosus received indomethacin intravenously. Plasma samples were collected at 2, 4, 6 or 8 and 12 h after each of 3 doses. Indomethacin, demethylindomethacin and p-chlorobenzoic acid were determined in plasma and urine along with acid-labile metabolites using HPLC. Fifty-eight percent of the infants demethylated indomethacin; half of the unchanged and demethylated drug was found as conjugates in urine; 14% deacylated the drug. Shorter elimination half-life, smaller area under the plasma concentration-time curves and increased plasma clearance were associated with demethylation. Postnatal age >2 weeks correlated with both demethylation and failure of indomethacin to effect ductal closure.

High efficacy and minor renal effects of indomethacin treatment during individualized fluid intake in premature infants with patent ductus arteriosus

“…In the study by van Overmeire et al (13), indomethacin was started with 0.2 mg kg À1 body weight on day 3 and repeated twice every 12 h. In contrast, Shaffer et al (12) used an individualized pharmacokinetic/pharmacodynamic dosing approach that is based on determinations of plasma indomethacin concentrations, calculation of pharmacokinetic parameters, and repeated evaluation of treatment effect and toxicity. With this approach, they effectively treated premature infants with increased indomethacin clearance due to advanced postnatal age (22). The results of the present study confirm the high rate of PDA closure by indomethacin demonstrated by van Overmeire et al and Shaffer et al (12,13).…”

Prenatal diagnosis of intrauterine premature closure of the ductus arteriosus following maternal diclofenac application

“…In some fetuses indomethacin will cause immediate constriction and possibly closure; in others the ductus can remain open despite repeated doses10. It has been argued that the pronounced difference in effect, in one case11 even observed in twins in which one infant suffered from ductal closure and the other's ductus remained open, is caused by different pathways of breakdown of the drug: by deacetylation or by demethylation12. Several other pharmacological agents have been known to cause ductal constriction; for example, betamethasone, applied to enhance fetal lung maturation, can cause transient reversible ductal constricition13.…”

Pharmacokinetics of indomethacin in sheep after intravenous and intramuscular administration

“…(1 mg/kg) and i.m. (1 mg/kg) administrations to sheep, as well as those reported in various domestic animals (Cociglio et al ., 1991; Cristofol et al ., 1996) and humans (Duggan et al ., 1972; Alvan et al ., 1975), including preterm infants (Friedman et al ., 1991), have been best described using a two‐compartment model.…”