UBC Theses and Dissertations
CNS pharmacokinetics of diphenhydramine in sheep Yeung, Sam Au
The CNS pharmacokinetics of the Hrreceptor antagonist, diphenhydramine (DPHM), was studied in 100 d (103.5 ± 1.7 d) and 120 d (124.1 ± 1.4 d) fetuses, 10 cl (11.5 ± 1.6 d) and 30 d (33.8 ± 1.2 d) newborn lambs, and adult sheep (5.21 ± 2.83 years) using in vivo microdialysis. The first study involved i.v. administration of DPHM at 5 infusion rates to the animals, with each step lasting 7 h. At all ages, CSF and ECF concentrations were very similar to each other, which suggested that the transfer of DPHM between these two compartments was by passive diffusion. Also, the brain-toplasma concentration ratios were 3 or higher in all age groups indicating the existence of an active transport process for DPHM into the brain. Both brain and plasma DPHM concentrations increased in a linear fashion over the dose range studied. Clj was the lowest in adult sheep, likely due to active renal tubular reabsorption of the drug. On the other hand, the factors f[sub csF] and f[sub ecF] decreased with age, indicating that DPHM was more efficiently removed from the brain as age increased. The extent of plasma protein binding of the drug increased with age. Vds s dropped postnatally in the newborn lambs and increased significantly in the adults. In the second study, DPHM was infused for 8 h and propranolol (PRN) was coinfused from 4 - 8 h. The purpose was to examine the effects of PRN on blood brain CSF and blood-brain ECF relationships. Pharmacokinetic analysis showed that CIT was not significantly different from that in the 5-step infusion study but AUC[sub brain]/AUC[sub piasma] ratios ( f[sub csF] and f[sub ecF]) increased in all age groups after PRN coadministration. On the other hand, protein binding was not changed by PRN. The observed increase in f ratios appears to be due to the inhibitory effects of PRN on a transporter-mediated mechanism for DPHM brain elimination. PRN also caused decreases in heart rate in all groups except the 100 d fetuses. In summary, these two studies suggest the existence of transporter-mediated mechanisms for the influx and efflux of DPHM into and out of the brain. While postulations have been made as to the possible identities of these transporters, further work is needed in order to obtain a definitive answer.
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