Secretion of drugs into the human female genital tract

Abstract

Drug disposition out of and into the female genital tract has received relatively little attention from clinical pharmacologists. This is surprising, for, at least in about 50% of the population, the vaginal route is available for parenteral drug administration. The systemic bioavailability of drugs after vaginal administration is much greater than after oral administration, not unexpectedly because the venous drainage of the vascular vaginal wall is directly into the inferior vena cava, so by-passing the hepatic circulation.'Propranolol has been successfully administered by the vaginal route in a patient unable to take it orally,2 and, recently, vaginal bromocriptine has been used successfully to treat a prolactinproducing pituitary tumour in a patient in whom side effects precluded oral administration of the drug.3 Subsequent studies in volunteers by the authors of this latter report showed that circulating levels of bromocriptine were significantly higher following vaginal than oral administration.The extent of secretion of drugs into the female genital tract after oral administration is important for several reasons. Firstly, a drug may exert its therapeutic action through its concentration in cervical mucus. For example metronidazole given orally can be used to treat vaginal trichomonas infections.4 Secondly, a drug may exert unwanted effects by reducing sperm motility and fertility.5 Orally administered propranolol has been shown to be highly concentrated in cervical mucus6 and other experiments have shown it to reduce sperm motility in vitro,7 although only at concentrations much higher than those achieved in cervical mucus after therapeutic oral doses. A preliminary study involving insertion of 80 mg propranolol tablets in the vaginas of 198 female volunteers has shown that propranolol is an effective vaginal contraceptive.8The extent to which a drug and its metabolites appear in human body fluids depends on their physicochemical properties, including lipid solubility, protein binding and dissociation constant. Some local factors may also influence their concentration in cervical mucus, including environmental pH and the concentrations of various proteins in the mucus. Albumin and alpha-1-acid glycoprotein (AGP) in serum play an important role in the binding of drugs, but their role in cervical mucus is obscure. The albumin concentration in cervical mucus is merely 1% of that in serum, and AGP is present only in traces during the mid-cycle period when it has been measured.9"10The protein-binding of propranolol and ibuprofen in cervical mucus has been found to be 26% and 66% respectively, and this has not correlated with the concentrations ofeither albumin or AGP.""2 It is unlikely, therefore, that cervical mucus protein concentration is an important determinant of drug disposition into cervical mucus.In order to determine the influence of the physicochemical properties of a drug, namely its lipid solubility, serum protein binding, and dissociation constant (pKa) on its cervical mucus concentration, we ha...