Blood–Placental Barrier Transfers and Pharmacokinetics of Unbound Morphine in Pregnant Rats with Multiple Microdialysis Systems

Abstract

Microdialysis coupled to an analytical system can be used to continuously monitor unbound protein analytes in any biological fluid, tissue, or organ of animals. To date, no application of microdialysis has been performed to simultaneously monitor unbound morphine and its metabolites in the placenta and fetus of pregnant rats. Our hypothesis is that morphine and its metabolite penetrate the blood–placental barrier to reach the fetus during pregnancy. To investigate this hypothesis, this study aimed to develop a microdialysis experimental animal model coupled with an analytical system to monitor morphine and morphine-3-glucuronide (M3G) in the maternal blood, placenta, fetus, and amniotic fluid of pregnant rats. To determine the analytes in dialysates, a validated ultra-high-performance liquid chromatography–tandem mass spectrometry (UHPLC-MS/MS) method was developed. The pharmacokinetic results indicated that morphine fit well to a two-compartment model and exhibited nonlinear pharmacokinetic behavior within the dosage regimen. The M3G-to-morphine metabolite ratio, determined by the area under the concentration curve (AUC) ratio (AUCM3G/AUCmorphine), was approximately 5.40 in the maternal blood. In terms of tissue distribution, the mother-to-fetus transfer ratio (AUCfetus/AUCblood) of morphine and M3G was about 0.34 and 0.18, respectively. In conclusion, the high metabolite ratio suggests that morphine has the characteristics of rapid biotransformation, and the mother-to-fetus transfer ratio indicates that morphine and M3G partially transfer the blood–placental barrier in pregnant rats. This newly developed multiple microdialysis coupled to UHPLC-MS/MS system can be applied to the studies of maternal pharmacokinetics and blood–placental transfer in pregnant rats.

Biotransformation and transplacental transfer of the anti-viral remdesivir and predominant metabolite, GS-441524 in pregnant rats

“…The multiple microdialysis system in the transplacental transfer model was implemented in line with our previous study. 13 The microdialysis module system comprised of a microinjection pump (CMA 400; CMA Microdialysis, Stockholm, Sweden) and a microinjection collector (CMA/142; CMA Microdialysis). The microdialysis probes were custom-made in-house.…”

“…Following a 1-hour stabilization period, remdesivir (30 mg/kg, 10% DMSO in PEG400) was administered intravenously through the femoral vein cannula. 13 Dialysis samples were collected every 20 min for 4 h and stored at -20°C until analysis using UHPLC-MS/MS.…”

Pharmacokinetic analysis of placental transfer of ritonavir as a component of paxlovid using microdialysis in pregnant rats

“…In order to determine the transplacental transfer ratio into the conceptus, our laboratory has made efforts in conventional sampling techniques [ 15 , 16 ], as well as microdialysis [ [17] , [18] , [19] , [20] ]. Microdialysis is a technique that uses probes with semipermeable membrane to sample endogenous and exogenous substances [ [21] , [22] , [23] ].…”