ABSTRACT
1. Urine samples from 20 premature neonates who received doxapram by i.v. infusion were analysed for drug metabolites by g.l.c-mass spectrometry. 2. In addition to doxapram, all urines contained at least one metabolite, but the known metabolite, 3-ketodoxapram, was detected in only 50% of the samples, and in some instances only in trace amounts. 3. Significant inter-individual differences in the metabolic pathways of doxapram were observed. 4. A total of six metabolites of doxapram were isolated three of which have not been observed previously in human or in dog. 5. Appropriate structures for the new metabolites have been deduced from their mass spectral fragmentation pathways, and are 1-ethyl-4-[2-(N-formyl-N-(2-hydroxy-ethyl)amino)ethyl]-3,3-diphenyl-2- pyrrolidinone (VII), 1-ethyl-4-[2-(4-morpholin-2-onyl)ethyl]-3,3-diphenyl-2-pyrro lidinone (IX) and 4-ethenyl-1-ethyl-3,3-diphenyl-2-pyrrolidinone (X).
Subject(s)
Doxapram/urine , Doxapram/chemistry , Doxapram/metabolism , Female , Gas Chromatography-Mass Spectrometry , Humans , Infant, Newborn , Infant, Premature , Male , Molecular StructureABSTRACT
Methods for the quantitation of doxapram in blood, plasma and urine have been developed. Following extraction, gas-liquid chromatography was used to separate doxapram from basic metabolites. Doxapram was detected by mass spectrometry for blood and plasma assays, and by flame ionisation for urine assays. The limit of reliable quantitation in blood and plasma was 10 ng and in urine 500 ng, the coefficients of variation being 6.37%, 1.72% and 2.31% respectively. To illustrate the clinical applicability of the assay methods, plasma, blood and urine levels were monitored in a premature newborn following an intravenous infusion of doxapram.
