Targeted drug delivery in gynaecology: the first uterine pass effect

The objective was to verify the hypothesis of a 'first uterine pass effect'or direct preferential vagina-to-uterus transport, suggested by theevidence of higher than expected uterine tissue concentrations aftervaginal administration of progesterone; we used a human ex-vivo uterineperfusion model. A mixture of tritiated (3H) and unlabelled progesteronewas applied to the cuff of vaginal tissue remaining attached to the cervixafter hysterectomy. At the end of the perfusion period (up to 12 h), 3H and14C radioactivity was measured in samples of uterine tissue. Tritiatedwater and [14C]dextran were tested to determine the extent of non-specificvagina-to-uterus transport (leaks). Finally, sections of uterine tissueexposed only to [3H]progesterone were prepared for autoradiography. By 4-5h after application progesterone had diffused to the entire uterus and hadreached a steady state; 4 h after application, progesterone concentrationsreached 185 +/- 155 and 254 +/- 305 ng/100 mg of endometrial and myometrialtissue respectively. Endometrial extraction of progesterone was higher whenthe experiment was performed on uteri obtained during the luteal phase (280+/- 156 ng/100 mg of endometrial tissue) than those removed during theproliferative phase of the menstrual cycle (74 +/- 28 ng/100 mg ofendometrial tissue). These data demonstrate that a 'first uterine passeffect' occurs when drugs are delivered vaginally, thereby providing anexplanation for the unexpectedly high uterine concentrations relative tothe low serum concentration observed after vaginal administration. Hence,the vaginal route permits targeted drug delivery to the uterus, therebymaximizing the desired effects while minimizing the potential for adversesystemic effects.