Foetal Fentanyl Exposure and Ion Trapping after Intravenous and Transdermal Administration to the Ewe.
Opioids given to pregnant and parturient women are relatively freely transferred across the placenta. Spinal, epidural and intravenous fentanyl has been studied in pregnant women and neonates, but foetal safety of fentanyl dosing with transdermal patch during pregnancy and labour is not sufficiently studied. Foetal pH is physiologically lower than maternal pH, and thus, opioids, which are weak bases, are ionized and may cumulate to foetus. Foetal asphyxia may further worsen acidosis, and ion trapping induced by low pH is assumed to increase the foetal exposure to opioids. Here, we show that no correlation between foetal acidosis and ion trapping of fentanyl could be found. In three experiments, 29 pregnant sheep were administered fentanyl with 2 μg/kg/h patch supplemented with IV boluses/infusion. Foetal exposure to fentanyl was extensive, median 0.34 ng/ml (quartiles 0.21, 0.42), yet drug accumulation to foetus was not observed, and median of foetal/maternal concentration (F/M) ratio was 0.63 (0.43, 0.75) during the first hours after the fentanyl administration. Low foetal pH and pH difference between ewe and the foetus did not correlate with fentanyl concentration in the foetus or F/M ratio. At steady-state during the second patch worn, foetal plasma fentanyl was low, 0.13 ng/ml, and the median of F/M ratio was 0.69. Our results demonstrate that drug accumulation to foetus caused by ion trapping seen with some weak base opioids may not be that significant with fentanyl. These results have a clinical relevance when fentanyl is dosed to pregnant woman and the foetus is acidemic.
School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
Emma M
EM
Heikkinen
Anaesthesia and Operative Services, Kuopio University Hospital, Kuopio, Finland.|School of Medicine, University of Eastern Finland, Kuopio, Finland.
Hannu
H
Kokki
Admescope Ltd, Oulu, Finland.
Aki
A
Heikkinen
School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
Veli-Pekka
VP
Ranta
School of Medicine, University of Eastern Finland, Kuopio, Finland.|Department of Obstetrics and Gynaecology, Kuopio University Hospital, Kuopio, Finland.|Department of Obstetrics and Gynaecology, Oulu University Hospital, Oulu, Finland.
Juha
J
Räsänen
Laboratory Animal Centre, Department of Experimental Surgery, University Hospital of Oulu, Oulu, Finland.
Hanna-Marja
HM
Voipio
Anaesthesia and Operative Services, Kuopio University Hospital, Kuopio, Finland.|School of Medicine, University of Eastern Finland, Kuopio, Finland.
Merja
M
Kokki
D000279:Administration, Cutaneous; D061605:Administration, Intravenous; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D005333:Fetus / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007273:Injections, Intramuscular; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D023421:Models, Animal; D011247:Pregnancy; D012756:Sheep; D014018:Tissue Distribution; D057968:Transdermal Patch
D000701:Analgesics, Opioid; D005283:Fentanyl