Received for publication November 27, 2006.
Revised May 2, 2007.
Accepted for publication May 3, 2007.

The use of microdialysis for the study of drug kinetics:CNS pharmacokinetics of diphenhydramine in fetal, newborn and adult sheep

Abstract

The CNS pharmacokinetics of the H₁-receptor antagonist, diphenhydramine (DPHM), were studied in 100 and 120 d fetuses, 10 and 30 d newborn lambs, and adult sheep using in vivo microdialysis. DPHM was administered i.v. at 5 infusion rates, with each step lasting 7 h. In all ages, CSF and ECF concentrations were very similar to each other, which suggest that DPHM transfer between these two compartments is by passive diffusion. Also, the brain-to-plasma concentration ratios were 3 in all age groups suggesting the existence of a transport process for DPHM into the brain. Both brain and plasma DPHM concentrations increased in a linear fashion over the dose range studied. However, the ECF/unbound plasma and CSF/unbound plasma DPHM concentration ratios were significantly higher in the fetus and lambs (~5-6) than in the adult (~3). The factors f_CSF and f_ECF, the ratios of DPHM AUCs in CSF and ECF to the plasma DPHM AUC, decreased with age, indicating that DPHM is more efficiently removed from the brain with increasing age. The extent of plasma protein binding of the drug increased with age. This study provides evidence for a transporter-mediated mechanism for the influx of DPHM into the brain and also for an efflux transporter for the drug, whose activity increases with age. Moreover, the higher brain DPHM levels in the fetus and lamb compared to the adult may explain the greater CNS effects of the drug at these ages.

Key words: blood-brain barrier, blood-CNS transport, developmental pharmacology, fetal drug metabolism