DISPOSITION OF A NEW RATE-CONTROLLED FORMULATION OF PRAZOSIN IN THE TREATMENT OF HYPERTENSION DURING PREGNANCY - TRANSPLACENTAL PASSAGE OF PRAZOSIN

Prazosin (PRZ) in conventional tablet form (P-CT) has the disadvantage s of a relatively short terminal half-life, a slight solubility in wat er and the well-recognized adverse effect of symptomatic orthostatic h ypotension. The pharmacokinetic study of a new rate-controlled formula tion of prazosin (Prazosin-Gastrointestinal System: P-GS) was performe d in 9 pregnant women during the third trimester (If pregnancy. Patien ts had persistent elevation of blood pressure. The subjects gave their informed consent for oral administration of] daily dose of 5 mg P-GS at 8 a.m. A first analysis period on day I enabled definition of the i nitial pharmacokinetic behavior of the drug, while the aim of a second was to evaluate its fate at plateau. The clinical course of both moth er and fetus was subsequently monitored. This was an open, non-randomi zed study, each patient serving as her own control. For 3 patients, we aimed to determine the possible transplacental passage of PRZ at deli very. PRZ levels were measured by HPLC and data were analysed by nonco mpartmental linear pharmacokinetic methods. The data show: (i) P-GS wa s well tolerated by all patients and there were no significant changes in fetal heart rate during the study. (ii) A significant decrease in diastolic blood pressure was observed after the 36th hour following th e first dose of P-GS while a reduction in systolic blood pressure was observed on day 4. (iii) An approximated relative bioavailability (f'( P-GS)) of 36.5% was calculated. P-GS appears to have a lower bioavaila bility than P-CT in women of similar gestational age. (iv) Both C-max and AUC(0-->infinity) are significantly increased at plateau. Further, terminal half-life is increased with regard to the value determined w ith P-CT. No accumulation of PRZ was noted at steady-state. (v) P-GS i s an example of an oral zero-order absorption product that offers one approach to control and improve the outcome of hypertensive therapy du ring pregnancy. This treatment could represent an alternative to methy ldopa as a first treatment of pregnancy-associated hypertension. (vi) There is a slight transplacental passage of the drug (of the order of 10-20%).