Placental transfer, lacteal transfer and plasma protein binding of gemcitabine

Abstract

1. The placental transfer, lacteal transfer and plasma protein binding of gemcitabine have been studied in rat and dog after single intravenous administration of 10 mg/kg 14C-gemcitabine. 2. Radioactivity was distributed to the foetuses at 5 min after administration to rat on days 12 and 18 of gestation. The concentrations of radioactivity in the foetal liver, lung and kidney on day 18 of gestation were 4.0-6.4 times higher than in the maternal blood at 4 h after administration. Relatively high levels of radioactivity were noted in foetal tissues 24 h after administration, indicating slow elimination from the foetus. 3. The concentration of radioactivity in milk reached a maximum at 15 min after administration to the lactating rat on day 10 after delivery, then declined in a biphasic manner, and was below the detection limit at 48 h. The concentrations of radioactivity in milk were lower than plasma concentrations of radioactivity. 4. Plasma protein binding ratios were 10-16 and 1-7% between 5 min and 8 h after administration to the male rat and dog respectively. When fresh plasma from male rat, dog and adult man was spiked with 14C-gemcitabine at concentrations of 0.1-25 micrograms/ml, the plasma protein binding ratios were about 7% in both rat and dog, and 10% in man.

Pharmacokinetics of gemcitabine and its primary metabolite in dogs after intravenous bolus dosing and its in vitro pharmacodynamics

“…The few available studies show that gemcitabine in plasma is freely available for intracellular transport as it is minimally plasma protein bound, with reported plasma protein binding values ranging from −2.5% to 7% (Shipley et al. , 1992; Esumi et al. , 1994a).…”

“…Limited pharmacokinetic (PK) studies have been conducted with gemcitabine in dogs. The few available studies show that gemcitabine in plasma is freely available for intracellular transport as it is minimally plasma protein bound, with reported plasma protein binding values ranging from )2.5% to 7% (Shipley et al, 1992;Esumi et al, 1994a). Elimination of gemcitabine occurs primarily through deamination by cytidine deaminase to the inactive metabolite 2¢,2¢-difluorodeoxyuridine (dFdU), which is then excreted in the urine (Shipley et al, 1992;Bouffard et al, 1993;Kawai et al, 1995;Plunkett, 1995).…”

Docetaxel, gemcitabine, and cisplatin administered for non-small cell lung cancer during the first and second trimester of an unrecognized pregnancy

“…Experimental animal studies have demonstrated that gemcitabine had both embryotoxic and fetotoxic effects, characterized by cleft palate, incomplete ossification, fusion of pulmonary artery, absence of gall bladder, decreased fetal viability, and developmental delays [16,17]. As of today, there is no report describing the outcome in humans receiving gemcitabine during pregnancy.…”

Manipulation of olfactory tight junctions using papaverine to enhance intranasal delivery of gemcitabine to the brain

“…After confirming that our IN drug delivery technique targeted the OE without toxicity to target and non-target tissues, we then used in vivo brain microdialysis to investigate the potential for PV to enhance delivery of IN-administered gemcitabine, a model nucleoside chemotherapeutic drug (Santoro et al, 2000; De Lange et al, 2004), to the CNS. Gemcitabine, our model drug, is a small (MW 299.66) polar molecule and has 7% plasma protein binding ratios in rat and dog and 10% in human (Esumi et al, 1994). Since it is a small hydrophilic molecule, it can be transported across the nasal epithelial TJs by paracellular transport.…”