Open Collections

Indomethacin : Capillary gas chromatographic-electron capture detection analysis and pharmacokinetic studies in the fetal lamb

University of British Columbia

Indomethacin is currently used in the treatment of patent ductus arteriosus, preterm labour, and for polyhydramnios. In order to investigate its clearance and disposition in the chronically instrumented ovine fetus, a sensitive assay was required. The developed GC-ECD method involves the extraction of indomethacin and a-methyl indomethacin, the internal standard, from acidified plasma, urine, amniotic and tracheal fluids using a simple one-step liquid-liquid extraction procedure with ethyl acetate. The organic extract is evaporated and the residue derivatised with N-methyl-N-(tert-butyldimethylsilyl)-trifluoroacetamide (MTBSTFA). The derivatised samples were reconstituted with toluene and aliquots of 2 jxL injected into the GC. Calibration curves were linear over the working range of 1-32 ng of indomethacin/mL with a coefficient of determination (r ) > 0.99, following extraction of 0.1 mL of plasma, and 0.1-1.0 mL of urine, amniotic and tracheal fluids. Mean recoveries from plasma and urine were 96.99 ± 9.25 % and 94.74 ± 6.75 %, respectively. The limit of quantitation is 1 ng/mL (< 10% C.V., S/N > 10).Inter- and intra-day variabilities at each concentration point were < 11 % for concentrations between 2-32 ng/mL and < 20 % at the LOQ of 1 ng/mL. Ill The mean steady state fetal femoral arterial concentration of indomethacin was 181.67 ± 45.05 ng/mL in the high dose group (n=5), and 41.29 ± 3.14 ng/mL in the low dose group (n=2). The arterio-venous concentration difference for indomethacin at apparent steady state was minimal but statistically significant, suggesting a low placental permeability to indomethacin in sheep. The fetal total body clearance was estimated to be 44.55 + 11.14 mL/min (n=7). The placental clearance of indomethacin, as determined by the Fick principle, was calculated to be 8.85 ± 0.81 mL/min/kg. The renal clearance was estimated to be 0.015 + 0.009 mL/min (n=5). Indomethacin appeared in very low concentrations in amniotic fluid and fetal urine in high dose group fetuses. It was not observed to accumulate in tracheal fluid. The drug appeared to induce lactic acidosis and a reduction in fetal urinary output in some fetuses of the high dose group.

Thesis/Dissertation

application/pdf

2009-01-11

For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.

http://hdl.handle.net/2429/3557

Pharmaceutical Sciences

University of British Columbia

UBCV

DSpace