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).
To examine the possibility of a pharmacokinetic interaction between doxapram
and theophylline, both drugs (1.5 mg/kg/h doxapram, and 0.5 mg/kg/h theophylline) were
administered in that order and in reverse order to patients with apnea of prematurity. During
the therapeutic steady state phase of doxapram considerable serum theophylline concentrations
were found despite discontinuation of the latter drug for at least 48 h. Serum doxapram
concentrations during theophylline steady state were negligible. Pretreatments of theophylline
failed to alter the pharmacokinetic indices of doxapram. Thus, a lack of pharmacokinetic
interaction between the two drugs was demonstrated.
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