| A population pharmacokinetic analysis using non-linear mixed effect modeling (NONMEM) was performed to characterize the pharmacokinetics of sotalol in 64 pediatric patients. Oral clearance and volume distribution were found to be age-dependent. Patients under one year of age showed a prolonged terminal half-life for sotalol, suggesting dosage modifications for patients in this age range with either a decrease of the dose or increase of the dosing interval. Body weight was found to be the best predictor of both oral clearance and volume distribution. Patients younger than one year of age needed further age-adjustment, as their clearance was even lower than predicted based on body weight.; The developmental pattern of Mdr1a and Mdr1b in rats two genes was tissue-specific and gene-specific. In the liver, Mdr1a expression was lower at birth and increased thereafter until reaching adulthood levels at 28 days. Mdr1b expression, however, was relatively high at birth. The maximal level was reached at 14 days postnatal age. In the kidneys, Mdr1a and Mdr1b had similar developmental patterns with gradually increased expression of both genes after day 3 except for expression differences at birth. The developmental patterns in the gastrointestinal tract were much different from the liver and kidney. Compared with expression at day 7 and day 21, at day 14 Mdr1a was expressed in duodenum/jejunum, ileum and colon at a relatively low level, whereas Mdr1b was highly expressed at day 14, although there were differences in the magnitude between different tissues. A potential explanation is that physiological changes including hormones and growth factors in suckling rats themselves as well as in maternal milk result in the observed variations in the regulation of Mdr1a and Mdr1b expression. In addition, residual maternal progesterone levels in newborns might explain upregulation of Mdr1b expression in newborns.; In human liver, MDR1, encoding for the transport protein P-glycoprotein, showed age-related expression. Hepatic MDR1 mRNA expression was significantly correlated with age in infants <1 yr, although this correlation did not result in statistically significant differences between our arbitrarily chosen age groups, probably because of the limited number of samples from newborns and young infants. |
