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Analysis, pharmacokinetics, metabolism and pharmacodynamics of labetalol in pregnant and nonpregnant sheep Yeleswaram, Krishnaswamy


Labetalol, a combined al and p-adrenoceptor blocker, is used as an antihypertensive, especially in the management of hypertensive disorders in pregnancy. While the antihypertensive efficacy of labetalol in pregnancy has been assessed by a number of clinical trials, there is little information in the literature about the disposition or pharmacodynamics of labetalol in the in utero fetus. Hence, a detailed investigation into the maternal-fetal pharmacokinetics and pharmacodynamics of labetalol was undertaken. Studies in adult nonpregnant sheep were also conducted to complement the data obtained from pregnant sheep. The maternal-fetal pharmacokinetics and pharmacodynamics of labetalol were studied in chronically instrumented pregnant sheep following a 100 mg i. vbolus. Labetalol was measured by a sensitive microbore high-performance liquid chromatographic assay with fluorescence detection, developed in this laboratory. The maternal total body clearance was 30.8 ± 3.83 in Umin/kg (mean ± SEM), elimination half-life was 2.79 ± 0.66 h and the volume of distribution at steady-state was 3.02 ± 0.18 LAT. Labetalol persisted in the amniotic and tracheal fluids up to 24 h. The fetal exposure to labetalol, calculated as the ratio of fetal to maternal area under the arterial plasma concentration-time curve, was equal to 14.4± 1.54%. Significant metabolic effects including maternal and fetal hyperglycemia and lactic acidosis and a decrease in fetal oxygen content were observed, suggesting potent r32-agonist activity. The lactic acidosis was more pronounced in the fetus than in the ewe. In adult nonpregnant sheep, a 100 mg i.v. bolus administration of labetalol caused hyperglycemia, lactic acidosis, a significant increase in femoral blood flow, hypotension and tachycardia. The net output of lactate from the hind limb was found to be 6.25 ± 1.35 g (0.07 ± 0.015 mol). The metabolism of labetalol was studied using the urine and bile samples obtained in this study. The cumulative urinary excretion of labetalol as unchanged drug, glucuronide and sulfate were found to be 1.61 ± 0.38, 11.46 ± 2.83 and 1.47 ± 0.74% of the dose, respectively. A sensitive and specific gas chromatographic assay with mass selective detection was developed to identify and quantitate 3-amino-l-phenylbutane, an oxidative metabolite of labetalol and a close structural analog of amphetamine. Using this assay, the metabolite was identified in the bile and urine samples. The cumulative urinary excretion of the oxidative metabolite was equivalent to 0.044 ± 0.016% of labetalol dose. The exact role of this metabolite in the mediation of labetalol pharmacodynamics remains to be investigated. The vasodilation caused by labetalol in adult sheep, appears to be a direct effect of this drug, with little or no involvement of a-blockade or P-agonism. In the fetal hind limb, however, labetalol did not produce any consistent vasodilation. The pharmacokinetics and pharmacodynamics of dilevalol, the RR-isomer of labetalol, were studied in two adult nonpregnant sheep following a 25 mg intravenous bolus and the results suggest that most of the pharmacodynamics of labetalol in sheep could be attributed to dilevalol. The pharmacokinetics, metabolism and pharmacodynamics of labetalol in the fetus following exposure to clinically relevant labetalol concentrations were studied after a 4 mg direct fetal i.v. bolus. The total body clearance (50.45 ± 1.37mL/min/kg), elimination half-life (4.35 ± 0.33 h) and apparent volume of distribution at steady-state (14.28 ± 0.95 L/kg) of labetalol in the fetal lamb were significantly higher than the corresponding values in the ewe following a 100 mg bolus. The calculated fetal transplacental clearance was 7.27 ± 2.11 mL/min/kg while the fetal nonplacental clearance was 43.18 ± 3.72 mL/min/kg. Glucuronide conjugates were present in the amniotic fluid samples, but sulphate conjugates and3-amino-l-phenylbutane, could not be identified in fetal plasma or amniotic fluid samples. Significant hyperglycemia and lactic acidosis were observed, but the magnitude of fetal lactic acidosis, calculated as the incremental increase in arterial lactate AUC (61.11 ± 15.59 mMh), was not significantly different from that observed following maternal administration (67.8 ± 7.26 mMh), despite a roughly four-fold higher fetal exposure to labetalol. The exact reasons for this discrepancy are not clear.

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