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Pharmacokinetics and conjugative metabolism of labetalol stereoisomers in pregnant sheep : a chiral drug case study in pregnancy

University of British Columbia

A chiral HPLC assay for the separation of the four stereoisomers of labetalol in biological fluids was developed. The limit of detection of the individual isomers was 0.15 ng (0.6 ng of injected racemic labetalol). In maternal plasma the concentration of the RR isomer was 25±12% higher than those of the SR, SS and RS isomers throughout the infusion and post infusion period. The RR isomer had the lowest steady-state clearance (50.93±4.64 mL/min/kg) and the longest half-life (5.60±0.86 h). Ofthe 280 mg of labetalol administered, 11.04±2.76 mg was excreted as unconjugated while 65.84±7.19 mg was excreted as glucuronide conjugate. Approximately 32% of the unconjugated labetalol was in the form of the RR isomer compared to 19% for the other isomers. In fetal plasma, the concentration of the RR isomer (24 ± 5 ng/mL at steady-state) was 50% higher than that ofthe SR (11.00±2.38 ng/mL), SS(13.02±3.04 ng/mL) and RS(12.05±2.85 ng/mL) isomers throughout the infusion and post-infusion period, while the concentration of the SR isomer was consistently lower over the same interval. The terminal elimination half-life (t)/2) and the mean residence time (MRT) ofthe RR isomer were 13.07 ± 4.02 h, and 17.19 ± 5.63 h, respectively. Labetalol fetal infusion studies were performed in four chronically instrumented pregnant ewes. In fetal plasma, the concentration of the RR isomer at steady-state was 51.22 ± 4.55 ng/mL, which was significantly higher than the other three isomers ([SR]- 30.33 ± 3.41 ng/mL, [SS]= 33.70 ± 3.22 ng/mL, [RS]=34.93 ± 2.75). The terminal elimination half-life (ti/2) of the RR isomer was 8.62 ± 2.85 li, which was significantly lower than that obtained following maternal infusion of labetalol. Ofthe 9,400 ug of labetalol administered, 73.79 ± 9.64 mg (0.80 + 0.10%) was excreted as unconjugated while 133.44 ± 25.20 mg (1.4%) was excreted as glucuronide. Pharmacokinetics, pharmacodynamics and conjugative metabolism of dilevalol were compared to those obtained previously for dilevalol from racemic labetalol infusion experiments . The results suggest that virtually all of the previously observed pharmacological effects of labetalol in non-pregnant sheep were elicited by dilevalol.

Thesis/Dissertation

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2009-06-29

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http://hdl.handle.net/2429/9860

Pharmaceutical Sciences

University of British Columbia

UBCV

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