Pharmacokinetics and metabolism of rectally administered paracetamol in preterm neonates.

AIM: To investigate the pharmacokinetics, metabolism, and dose-response relation of a single rectal dose of paracetamol in preterm infants in two different age groups. METHODS: Preterm infants stratified by gestational age groups 28-32 weeks (group 1) and 32-36 weeks (group 2) undergoing painful procedures were included in this study. Pain was assessed using a modified facies pain score. RESULTS: Twenty one infants in group 1 and seven in group 2 were given a single rectal dose of 20 mg/kg body weight. Therapeutic concentrations were reached in 16/21 and 1/7 infants in groups 1 and 2, respectively. Peak serum concentrations were significantly higher in group 1. Median time to reach peak concentrations was similar in the two groups. As serum concentration was still in the therapeutic range for some infants in group 1, elimination half life (T1/2) could not be determined in all infants: T1/2 was 11.0 +/- 5.7 in 11 infants in group 1 and 4.8 +/- 1.2 hours in group 2. Urinary excretion was mainly as paracetamol sulphate. The glucuronide:sulphate ratio was 0.12 +/- 0.09 (group 1) and 0.28 +/- 0.35 (group 2). The pain score did not correlate with therapeutic concentrations. CONCLUSIONS: A 20 mg/kg single dose of paracetamol can be safely given to preterm infants in whom sulphation is the major pathway of excretion. Multiple doses in 28-32 week old neonates would require an interval of more than 8 hours to prevent progressively increasing serum concentrations.

Discrepancies in lipolytic activities induced by beta-adrenoceptor agonists in human and rat adipocytes.

A number of catecholamine and non-catecholamine beta-adrenoceptor agonists, including the lipolytically selective compound BRL 37344, were compared for lipolytic activity on human and rat adipocytes. On rat adipocytes, all compounds were full agonists, BRL 37344 being the most potent. On human adipocytes, only the catecholamines were full beta-adrenoceptor agonists. The other compounds were partial agonists, with intrinsic activities declining in the order fenoterol greater than salbutamol greater than clenbuterol greater than BRL 37344. This was the case with FFA- as well as with glycerol-production. Addition of 20 microM phentolamine did not enhance BRL 37344 activity. The isoprenaline- and BRL 37344-induced lipolysis on rat white adipocytes was stereoselectively antagonized by enantiomers of alprenolol, with atypical low potencies and stereoselectivity. It was concluded that (1) human and rat adipocyte beta-adrenoceptors mediating lipolysis are not essentially different, (2) partial agonism in human adipocytes is not explained by enhanced re-esterification and (3) BRL 37344 selectively stimulates rat adipocyte lipolysis.