The use of microdialysis for the study of drug kinetics: central nervous system pharmacokinetics of diphenhydramine in fetal, newborn, and adult sheep.

The central nervous system (CNS) pharmacokinetics of the H(1) receptor antagonist diphenhydramine (DPHM) were studied in 100- and 120-day-old fetuses, 10- and 30-day-old newborn lambs, and adult sheep using in vivo microdialysis. DPHM was administered i.v. at five infusion rates, with each step lasting 7 h. In all ages, cerebrospinal fluid (CSF) and extracellular fluid (ECF) concentrations were very similar to each other, which suggests that DPHM between these two compartments is transferred by passive diffusion. In addition, the brain-to-plasma concentration ratios were >or=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 (approximately 5 to 6) than in the adult (approximately 3). The factors f(CSF) and f(ECF), the ratios of DPHM areas under the curves (AUCs) in CSF and ECF to the plasma DPHM AUC, respectively, 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 with the adult may explain the greater CNS effects of the drug at these ages.

A pharmacokinetic study of diphenhydramine transport across the blood-brain barrier in adult sheep: potential involvement of a carrier-mediated mechanism.

The purpose of this study was to examine the disposition of diphenhydramine (DPHM) across the ovine blood-brain barrier (BBB). In six adult sheep, we characterized the central nervous system (CNS) pharmacokinetics of DPHM in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) using microdialysis in two experiments. In the first experiment, DPHM was administered via a five-step i.v. infusion (1.5, 5.5, 9.5, 13.5, and 17.5 microg/kg/min; 7 h per step). Average steady-state CNS/total plasma concentration ratios (i.e., [CNS]/[total plasma]) for steps 1 to 5 ranged from 0.4 to 0.5. However, average steady-state [CNS]/[free plasma] ratios ranged from 2 to 3, suggesting active transport of DPHM into the CNS. Plasma protein binding averaged 86.1 +/- 2.3% (mean +/- S.D.) and was not altered with increasing drug dose. Plasma, CSF, and ECF demonstrated biexponential pharmacokinetics with terminal elimination half-lives (t1/2beta) of 10.8 +/- 5.4, 3.6 +/- 1.0, and 5.3 +/- 4.2 h, respectively. The bulk flow of CSF and transport-mediated efflux of DPHM may explain the observed higher CNS clearances. In the second experiment, DPHM was coadministered with propranolol (PRN) to examine its effect on blood-brain CSF and blood-brain ECF DPHM relationships. Plasma total DPHM concentration decreased by 12.8 +/- 6.3% during PRN, whereas ECF and CSF concentrations increased (88.1 +/- 45.4 and 91.6 +/- 34.3%, respectively). This increase may be due to the inhibitory effect of PRN on a transporter-mediated efflux mechanism for DPHM brain elimination.

Maternal fluoxetine infusion does not alter fetal endocrine and biophysical circadian rhythms in pregnant sheep.

OBJECTIVE: Depression during pregnancy is frequently treated with the selective serotonin reuptake inhibitor (SSRI), fluoxetine (FX), commonly known as Prozac (Eli Lilly & Co, Indianapolis, IN). FX potentiates serotoninergic neurotransmission and serotonin has been implicated in the regulation of circadian rhythms. We have therefore investigated the effect of chronic administration of FX on maternal and fetal circadian rhythms in sheep. METHODS: Following an initial bolus dose of 70 mg FX, an 8-day continuous infusion of FX (n = 11, 98.5 microg/kg x d) was performed. Controls (n = 13) were treated with sterile water vehicle only. Maternal and fetal plasma melatonin and prolactin concentrations were determined every 3 hours for 24 hours and then every 6 hours for 24 hours beginning on the fourth day of infusion. RESULTS: FX treatment did not alter either the basal or circadian rhythms of either maternal or fetal plasma melatonin and prolactin concentrations. Fetal cardiovascular and behavioral state parameters were measured continuously. While the incidence of low-voltage (LV) electrocortical (ECOG) activity was significantly reduced in fetuses in the FX group, there was no effect of FX on the diurnal rhythms in fetal arterial pressure, heart rate, breathing movements, or behavioral state. CONCLUSION: These results show that maternal FX treatment does not result in significant alterations in maternal and fetal hormonal and behavioral circadian rhythms.

Chronic maternal fluoxetine infusion in pregnant sheep: effects on the maternal and fetal hypothalamic-pituitary-adrenal axes.

Depression during pregnancy is frequently treated with the selective serotonin reuptake inhibitor, fluoxetine (FX). FX increases serotonergic neurotransmission and serotonin plays a role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. We have therefore investigated the effect of chronic administration of FX to the pregnant ewe on the maternal and fetal HPA axes. Nineteen late-gestation sheep were surgically prepared for chronic study of the fetus. FX (n = 7, 98.5 microg/kg/d) or sterile water (control, n = 8) was administered to the ewe for 8 d by constant rate i.v. infusion with an initial FX bolus dose of 70 mg. Maternal and fetal plasma ACTH and cortisol concentrations were determined at 0700 h each day. Maternal plasma ACTH concentrations fell on infusion d 2, but no changes were observed in maternal plasma cortisol concentrations. Fetal plasma ACTH concentrations increased on infusion d 7, and fetal plasma cortisol concentrations increased on infusion d 6, 7, and 8 in the FX group. In addition, the regression coefficient for the relationship between fetal ACTH and cortisol levels was significantly greater in the FX group compared with the control group. Thus, maternal FX treatment increased fetal plasma cortisol concentration. These results are of particular interest in the context that exposure of the fetus to excess glucocorticoids at critical windows during development has been shown to increase the risk of poor health outcomes in later life.

Effect of maternal fluoxetine administration on uterine blood flow, fetal blood gas status, and growth.

Clinical depression, diagnosed in 5-15% of women during pregnancy, increases the risk of negative pregnancy outcomes including an increased incidence of low birth weight newborns and preterm delivery. Fluoxetine, a selective serotonin reuptake inhibitor, is often prescribed to treat depression due to its efficacy, high margin of safety, and mild side effects. However, fluoxetine initially increases plasma serotonin concentration, and serotonin causes uterine vasoconstriction in sheep, which could result in fetal hypoxemia. To assess fetal fluoxetine effects, late-gestation pregnant sheep were surgically prepared for the measurement of blood gases, heart rate, blood pressure, and uterine artery blood flow (n = 29). Ewes received a 70-mg bolus i.v. infusion of fluoxetine over 2 min in 10 mL of sterile water followed by continuous infusion at a rate of 100 microg/min for 8 d (n = 14), or continuous infusion of sterile water (n = 15). Transient decreases in uterine artery blood flow, fetal PO(2), and oxygen saturation were observed within the first 15 min after fluoxetine exposure, which did not return to normal values by 24 h. Fetal pH decreased and PCO(2) increased over the first 4 h with a return to normal by 24 h. However, there were no differences in uterine artery blood flow, blood gas status, or cardiovascular measures between the control and fluoxetine group over the rest of the 8-d infusion period. Thus, fluoxetine exposure during pregnancy has transient effects on fetal status that may be of developmental consequence if they occur repetitively.