Pharmacokinetics and Pharmacodynamics of TRH During Pregnancy REKHA BAJORIA, PhD, MRCOG, EUGENE OTENG-NTIM, MBBS, MICHAEL J. PEEK, PhD, FRACOG, AND NICHOLAS M. FISK, PhD, FRACOG Objective: To determine the pharmacokinetics and pharma- codynamics of thyrotropin-releasing hormone (TRH) in pregnant women. Methods: Twenty-four pregnant and eight nonpregnant women were given 400 ~g TRH as either intravenous infu- sion or bolus. Serial venous samples were collected for TRH, TSH, thyroxine, and prolactin assay. Results: When given as bolus, mean (± standard error of the mean) peak plasma concentration (50 + 5.2 and 73 ± 5.1 ng/mL, P < .01), elimination half life (4.3 + 0.3 and 6.3 ± 0.4 minutes, P < .001), and area under the curve (156.4 ± 14.8 and 340.1 ± 32.8 ng/mL/minute, P < .001) in pregnant subjects were reduced compared with controls, whereas plasma clearance (45.4 ± 6.5 and 23.6 ± 2.1 mL/kg/minute, P < .01) and volume of distribution (27.8 + 1.8 and 19.0 ± 1.3% body weight, P < .01) were increased. When given by infusion, steady-state concentration (6.6 ± 0.5 and 9.8 ± 0.9 ng/mL, P < .01) and elimination half-life (4.6 ± 0.5 and 6.3 +-- 0.3 minutes, P < .05) were lower in pregnant subjects than in controls. Thyrotropin-releasing hormone kinetics were inde- pendent of mode of administration. Although basal TSH and thyroid hormone concentrations were similar in patients and controls, the TSH response to TRH was blunted in pregnant subjects compared with controls (9.3 ± 0.6 and 16.4 ± 1.4/~IU/mL, P < .001). The basal (3187 ± 488 and 147 + 16 mIU/L) and maximal prolactin response (6193 ± 426 and 1316 ± 106 mlU/L) were increased in pregnant subjects compared with controls (P < .001). Conclusion: The peak plasma concentration and elimina- tion half-life of TRH are reduced during pregnancy because of the increased volume of distribution and rapid clearance. Mode of administration does not affect TRH pharmacokinet- ics, but the maternal pharmacodynamic response differs in patients receiving bolus compared with infusion. (Obstet Gynecol 1997;90:176-82. © 1997 by The American College of Obstetricians and Gynecologists.) From the Royal Postgraduate Medical School, Institute of Obstetrics and Gynaecology, Queen Charlotte's and Chelsea Hospital, London. This work was supported by a project grant from Action Research. We are grateful to Dr. H. Fraser,MRC unit of Reproductive Medicine, Edinburgh, for providing antirabbit TRH antibody. Thyrotropin-releasing hormone (TRH) is used in con- junction with corticosteroids to promote surfactant syn- thesis in the fetal lung. 1 Randomized, controlled trials of this transplacental fetal therapy to prevent respira- tory distress syndrome show conflicting results. 1-3 One explanation may be differing dose regimens. One re- port 1 found the most benefit in reducing the incidence and severity of respiratory distress syndrome by using 400 ~g TRH, whereas a larger study 3 showed no beneficial effect by using 200 ~g, suggesting that the fetal thyrotropic response to maternal TRH may be dose-dependent. Because TRH is degraded rapidly in maternal blood, 4 a high dose might be required to attain therapeutic levels in the mother. However, in the ab- sence of data on the pharmacokinetics of TRH in pregnant women, the optimum dose, frequency, and mode of administration to potentiate fetal lung matu- ration remain unclear. Current obstetric practice is based on giving TRH at a dose known in nonpregnant subjects to elicit maximal thyrotropic response. This assumes that the pharmaco- kinetics of TRH remain unchanged during pregnancy. However, it seems likely that the physiologic changes during pregnancy alter the kinetics of TRH. The half- life, volume of distribution, metabolism, and clearance of many drugs are altered during pregnancy. 5'6 In- creased maternal plasma volume, renal blood flow, and glomerular filtration rate can decrease peak plasma concentration by 30% and increase clearance of drugs by 30-50%. 5-7 In addition, the placenta and fetus rep- resent complex compartments that may alter the distri- bution of drugs. The rate of placental transfer of most drugs depends on the maternal integrated plasma con- centration time value and peak plasma concentration. 6'7 Therefore, any alteration in maternal pharmacokinetics is likely to influence transplacental passage of TRH and, by inference, the fetal thyrotropic response. We studied the pharmacokinetics and pharmacodynamics of TRH 176 0029-7844/97/$17.00 Obstetrics & Gynecology PII s0029-7844(97)00221-4