Cervidil Pharmacology, Pharmacokinetics, Studies, Metabolism - Dinoprostone

Cervidil Pharmacology, Pharmacokinetics, Studies, Metabolism - Dinoprostone

CLINICAL PHARMACOLOGY

Dinoprostone (PGE ₂ ) is a naturally-occurring biomolecule. It is found in low concentrations in most tissues of the body and functions as a local hormone (1-3). As with any local hormone, it is very rapidly metabolized in the tissues of synthesis (the half-life estimated to be 2.5-5 minutes). The rate limiting step for inactivation is regulated by the enzyme 15-hydroxyprostaglandin dehydrogenase (PGDH) (1,4). Any PGE ₂ that escapes local inactivation is rapidly cleared to the extent of 95% on the first pass through the pulmonary circulation (1,2).

In pregnancy, PGE ₂ is secreted continuously by the fetal membranes and placenta and plays an important role in the final events leading to the initiation of labor (1,2). It is known that PGE ₂ stimulates the production of PGF ₂ (alpha) which in turn sensitizes the myometrium to endogenous or exogenously administrated oxytocin. Although PGE ₂ is capable of initiating uterine contractions and may interact with oxytocin to increase uterine contractility, the available evidence indicates that, in the concentrations found during the early part of labor, PGE ₂ plays an important role in cervical ripening without affecting uterine contractions (5-7). This distinction serves as the basis for considering cervical ripening and induction of labor, usually by the use of oxytocin (8-10), as two separate processes.

PGE ₂ plays an important role in the complex set of biochemical and structural alterations involved in cervical ripening. Cervical ripening involves a marked relaxation of the cervical smooth muscle fibers of the uterine cervix which must be transformed from a rigid structure to a softened, yielding and dilated configuration to allow passage of the fetus through the birth canal (11-13). This process involves activation of the enzyme collagenase, which is responsible for digestion of some of the structural collagen network of the cervix (1,14). This is associated with a concomitant increase in the amount of hydrophilic glycosaminoglycan, hyaluronic acid, and a decrease in dermatan sulfate (1). Failure of the cervix to undergo these natural physiologic changes, usually assessed by the method described by Bishop (15,16), prior to the onset of effective uterine contractions, results in an unfavorable outcome for successful vaginal delivery and may result in fetal compromise. It is estimated that in approximately 5% of pregnancies the cervix does not ripen normally (17). In an additional 10-11% of pregnancies, labor must be induced for medical or obstetric reasons prior to the time of cervical ripening (17).

The delivery rate of PGE ₂ in vivo is about 0.3 mg/hour over a period of 12 hours. The controlled release of PGE ₂ from the hydrogel insert is an attempt to provide sufficient quantities of PGE ₂ to the local receptors to satisfy hormonal requirements. In the majority of patients, these local effects are manifested by changes in the consistency, dilatation and effacement of the cervix as measured by the Bishop score. Although some patients experience uterine hyperstimulation as a result of direct PGE ₂ - or PGF ₂ (alpha)-mediated sensitization of the myometrium to oxytocin, systemic effects of PGE ₂ are rarely encountered. The insert is fitted with a biocompatible retrieval system which facilitates removal at the conclusion of therapy or in the event of an adverse reaction.

No correlation could be established between PGE ₂ release and plasma concentrations of PGE _m . The relative contributions of endogenously and exogenously released PGE ₂ to the plasma levels of the metabolite PGE _m could not be determined. Moreover, it is uncertain as to whether the measured concentrations of PGE _m reflect the natural progression of PGE _m concentrations in blood as birth approaches or to what extent the measured concentrations following PGE ₂ administration represent an increase over basal levels that might be measured in control patients.

CLINICAL STUDIES