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Metoclopramide : fused-silica capillary GLC-ECD; placental transfer in humans and sheep

University of British Columbia

Metoclopramide (MCP), a procainamide derivative, is a potent antiemetic and gastric motility stimulator. It is used clinically to facilitate certain gastrointestinal diagnostic procedures, to treat a variety of gastrointestinal disorders and as an antiemetic in the treatment of nausea and vomiting of varying etiologies. MCP is also used parenterally prior to general anaesthesia in labour where its antiemetic properties and ability to promote gastric emptying help to reduce the incidence of aspiration of stomach contents and death due to Mendel son's Syndrome. This thesis reports the modification of an existing packed column electron-capture gas-liquid chromatographic (GLC-ECD) assay for MCP in human plasma (Tam et al., 1979). The reasons for changes to the method are discussed and illustrated. Components interfering with MCP estimation could not be resolved using packed column technology; a fused silica capillary GLC-ECD procedure was developed to overcome this problem. The method involves the extraction of MCP and maprotiline (MAP), the internal standard, from alkalinized plasma, followed by an acid back-extraction into benzene. The benzene extract is dried under a gentle stream of nitrogen and reconstituted with toluene. MCP and MAP are derivatized at 55°C with heptafluorobutyric anhydride (HFBA) in the presence of the catalyst, triethylamine (0.05 M). Excess HFBA is removed by hydrolysis with water and neutralization with 4% ammonium hydroxide. The derivatized organic layer is immediately removed from the aqueous phase for neutralization and 2 μL aliquots injected into a reporting gas-liquid chromatograph equipped with a ⁶³Ni electron-capture detector. The samples may be injected on the day of preparation or can be stored at -20°C for up to 4 days for subsequent analysis. Quantitation of MCP in test samples is made from a calibration curve prepared from plasma extracts containing known concentrations of MCP and MAP. A 25 m x 0.31 mm I.D. cross-linked fused silica capillary column was used for all quantitative plasma MCP analyses. Linearity was observed in the range of 4-40 ng of MCP base.mL⁻¹ following the extraction of 0.25-0.5 mL of plasma. This represents from ≃0.9-9 pg at the detector employing the split mode of sample injection (split ratio, 30:1) and an injection volume of 2 μL. The developed capillary assay method is sensitive, specific and selective. It has been found to be suitable for small volume plasma analysis in humans and sheep, has been applied to patient samples in the clinical setting without interference from the other drugs used in the study and has shown pharmacokinetic applicability to the study of MCP placental transfer in sheep. MCP was observed to undergo placental transfer in both humans and sheep following i.v. maternal administration. Twenty-three patients undergoing general anaesthesia for Caesarian section for healthy term pregnancies were included in the human study. The patients received either i.v. MCP or a normal saline placebo on a double-blind basis. Maternal and fetal (umbilical cord) plasma concentrations were measured and an average fetalrmaternal MCP concentration ratio (F/M) of 0.60 ± 0.17 determined. Apgar testing and thorough chart reviews were conducted to attempt evaluation of neonatal response to MCP. There were no significant differences between the treated and untreated groups of neonates. The in utero placental transfer of MCP to the fetus of a chronically catheterized pregnant ewe was also studied. Measurable concentrations appeared in the fetal circulation within 1 minute, peaked at 20 minutes and exceeded maternal levels at about 90 minutes. Maternal plasma MCP concentrations were observed to follow a biexponent!al decay. Terminal elimination half-lives of 40 and 54 minutes were calculated for MCP in the ewe and fetus, respectively.

Text

2010-04-22

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http://hdl.handle.net/2429/24020

Pharmaceutical Sciences

University of British Columbia

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