Placental transfer of theophylline in an in vitro closed perfusion system of human placenta isolated lobule

Abstract

Theophylline (TH) is a methylated xanthine widely used in the treatment of asthmatic pregnant women. Because of the scant available information on the transplacental profile, the time course of TH transfer was studied by an in vitro human placental perfusion. 6 placentas were perfused with Earle's enriched bicarbonate buffer for 180 min using recirculating maternal and fetal circuits. The physiological and biochemical properties of the tissue were well maintained. TH data were compared to those of antipyrine (AP), an usual marker in placental perfusions. The disappearance of TH from the maternal circuit was studied after administration of 15 mg/l in maternal perfusate. TH appeared in the fetal circuit within 5 min. Equilibrium was achieved in both circuits. TH fetomaternal mass ratio became constant (FMM = 0.45 +/- 0.01) after 80 min of perfusion and maternal to fetal clearance was 2.59 +/- 0.24 ml/min. About 16% of TH maternal dose was recovered in the tissue, while 18% appeared in fetal circulation. TH recovery was 89 +/- 9%. On the basis of our results, similar concentrations could be predicted in mother and fetus after maternal TH intake. The TH transfer profile is consistent with in vivo values reported in humans and animals at delivery.

Theophylline Pharmacokinetics in Foetal Sheep: Maternal Metabolic Capacity is the Principal Driver

“…This observation of a foetal‐to‐maternal concentration ratio less than one at equilibrium has been noted with valproic acid, diphenhydramine, morphine and methadone with a similar pregnant sheep model . Ex vivo perfusion experiments with placental lobules have observed slightly higher theophylline concentrations in maternal compared to foetal perfusate . Foetal metabolic clearance, protein binding, drug transporters and tissue permeability are all factors thought to contribute to differences between maternal and foetal concentrations at equilibrium .…”

“…Ex vivo perfusion experiments with placental lobules have observed slightly higher theophylline concentrations in maternal compared to foetal perfusate . Foetal metabolic clearance, protein binding, drug transporters and tissue permeability are all factors thought to contribute to differences between maternal and foetal concentrations at equilibrium . To explain the lower foetal concentrations at equilibrium, we first examined in vitro CYP1A activity in foetal and maternal tissues.…”

“…We speculate that theophylline is transported across the ovine placenta towards the maternal circulation. Theophylline, a highly lipid soluble drug, is a weak acid (pKa = 8.7 ), is predominately un‐ionized at physiological pH and is assumed to cross the placenta via passive diffusion . However, theophylline is a substrate for human organic anion transporter 2 (hOAT2 ), and methylxanthines have been shown to be inhibitors of hOAT1 and hOAT3 .…”

Medication induced fetal bladder rupture: a case report

“…It is thought that theophylline inhibits contractility of the detrusor muscle by increasing cyclic adenine monphos phate [6]. Theophylline crosses the placenta rapidly, with a similar concentration in the mother and fetus [7]. Maternal furosemide has been used to distend the fetal bladder for evaluation of urinary tract anomalies [8].…”

Pharmacokinetic examination of antipyrine passage through the placenta and the small intestine in rats

“…However, a statement as to whether a drug crosses the placenta or not is not sufficient any longer and there is an increasing effort to achieve a more precise description of the transplacental passage of various compounds. However, with the exception of a few workers (16,17) most researchers still limit their results only to the basic parameter of placental clearance which is very important but cannot entirely characterise the kinetics of this process.…”