ABSTRACT
The influence of morphine (MOR) on the pharmacokinetics and toxicity of repeated etoposide (ETP) oral administration was evaluated in rats. A decrease in the number of leukocytes in blood was observed by 5 days of treatment with ETP (30 mg/kg/day), which was prolonged by oral MOR coadministration (30 mg/kg/day). Furthermore, MOR significantly decreased animal viability. During the dosing period, the individual plasma ETP concentrations decreased at every dose. These doses were used to estimate the individual pharmacokinetic parameters by the Bayesian method using a linear 2-compartment model with a first-order kinetic absorption and the population parameters reported in our previous study. As a result, repeated ETP dosing without MOR showed a significant decrease in the intestinal absorption rate constant (ka), and single MOR coadministration induced an increase in bioavailability (F) and decrease in ka. However, repeated coadministration of ETP suppressed the increase of F by MOR, and the dose-normalized area under the concentration-time curve was not significantly decreased. The estimated trough concentration in the final day of coadministration was significantly higher than that of the control treatment and indicated a prolonged exposure time. These changes in the absorption of ETP may be closely related to variation in P-glycoprotein (P-gp) activity in the intestine and indicate that the pharmacokinetics and toxicity of ETP are altered by repeated oral coadministration of MOR.
Subject(s)
Etoposide/adverse effects , Etoposide/pharmacokinetics , Morphine/adverse effects , Morphine/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , Administration, Oral , Animals , Bayes Theorem , Biological Availability , Etoposide/administration & dosage , Intestinal Absorption/physiology , Intestinal Mucosa/metabolism , Male , Morphine/administration & dosage , Rats , Rats, WistarABSTRACT
Under acute stress conditions in the rat, there is rapid and transient increase in circulating prolactin (PRL). This leads to an elevated expression of the long form of PRLR (PRLR-L) first in the hypothalamus and the choroid plexus. This increase in PRL is involved in the inhibition of stress-induced hypocalcemia and gastric erosion. In this study we used rat PRL and a PRLR morpholino-antisense oligonucleotide to elucidate the mechanism by which hypothalamic PRLR mediates the inhibition of restraint stress in water (RSW)-induced hypocalcemia and gastric erosion. We found that this effect is largely mediated by PRLRs in the paraventricular nucleus (PVN), medial preoptic nucleus, and ventromedial hypothalamus. We also show that when measured after 7 h of RSW, microinjection of the PRLR antisense oligonucleotide into these areas down-regulates RSW-enhanced expression of PRLR-L protein in the PVN and increases the plasma PRL level, but does not affect plasma levels of another hormone, GH. Furthermore, our experiments demonstrated that under nonstress conditions, knockdown of the PRLR in the PVN significantly lowers circulating Ca2+ levels, but does not affect gastric erosion. These results suggest that PRL acting on the PRLR-L in the PVN is one of the critical pathways for regulating circulating Ca2+ levels under both acute stress and nonstress conditions.
