Transport kinetics of cisplatin in the perfused human placental lobule in vitro

Abstract

Objective. Platinum-containing drugs are used extensively in the treatment of various malignancies in humans. Data are scarce on the maternal–fetal transport characteristics in humans of one such widely used drug, cisplatin, and this prompted us to study its transport characteristics in the human placenta in vitro.Methods. Placentae from normal pregnancies were collected after delivery. Cisplatin, along with antipyrine as an internal reference marker, was injected as a single bolus (100 μL) into the maternal arterial circulation of isolated perfused placental lobules and perfusate samples collected from both maternal and fetal circulations over a period of 5 minutes. National Culture and Tissue Collection medium, diluted with Earle's buffered salt solution, was used as the perfusate. The concentration of cisplatin in various samples was determined by atomic absorption spectrophotometry, while antipyrine concentration was quantified by spectrophotometry. Transport and pharmacokinetic data of study and reference substances were computed using appropriate parameters.Results. The differential transport rate of cisplatin for 10, 25, 50, 75, and 90% efflux fractions in fetal venous effluent averaged 0.49 ± 0.02, 1.23 ± 0.03, 2.41 ± 0.04, 3.67 ± 0.03, and 4.48 ± 0.07 minutes in 12 perfusions, while corresponding rates for antipyrine, for above mentioned efflux fractions averaged 0.51 ± 0.01, 1.26 ± 0.05, 2.52 ± 0.01, 3.78 ± 0.01, and 4.52 ± 0.01 minutes, respectively. Cisplatin transport rates averaged 0.97, 0.97, 0.96, 0.97, and 0.99 times the antipyrine reference value. Analysis of variance (ANOVA) did not show any significant difference (p > 0.05) between the control and study group data. The transport fraction (TF) of cisplatin, expressed as a fraction of the drug appearing in the fetal vein during a study period of 5 minutes, averaged 9.00 ± 0.52% of bolus dose, while antipyrine TF averaged 68.6 ± 2.01% of injected bolus dose, representing 13.10% of reference marker value. The Student's t-test showed cisplatin and reference marker TF values to be significantly different (p < 0.05). Pharmacokinetic parameters such as area under the curve, clearance, absorption rate, and elimination rate of study and reference substances also varied significantly (p < 0.05).Conclusions. We report for the first time that cisplatin transport is negligible in the human placenta at term. It is reasonable to assume that the risk for the neonate from cisplatin use in pregnancy is minimal when it is used in emergency clinical situations.