Targeted drug delivery in gynaecology: the first uterine pass effect

Abstract

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

A Randomized Trial of Progesterone in Women with Recurrent Miscarriages

“…We studied a vaginal preparation of progesterone, at a dose of 400 mg twice daily, and it is possible that the results with this regimen are not generalizable to patients receiving other doses and preparations. However, we chose this route to deliver a greater proportion of the drug to the biologically relevant site (i.e., the uterus), 13,14 and the dose used (400 mg twice daily) represents a dose at the top end of the therapeutic window. 15 Some researchers have suggested that intramuscular preparations of progesterone may provide greater therapeutic benefit than vaginal preparations; however, data are lacking to support this contention, and previous trials of alternative progesterone preparations (including intramuscular progesterone) have shown varying results.…”

The efficacy of two different doses of vaginal isosorbide mononitrate in pre induction cervical ripening: a double blind randomised controlled trial

“…Vaginal administration of ISMN has been shown to result in lower plasma levels with peak levels being achieved only after 6 hours or more [14]. However, vaginal ISMN is thought to have its effects on the cervix much earlier due to the direct transport of the ISMN from the vagina to the cervix [14,16,17].…”

Current scientific and practical luteal phase support strategies

“…Возможны четыре механизма «первичного прохож-дения прогестерона в матку» при интравагинальном использовании микронизированного прогестерона: 1) прямая диффузия через ткани [31]; 2) пассаж прогестерона через цервикальный ка-нал из влагалища в полость матки [32];…”

“…[35] на экстирпированных матках, подключенных к перфузионной системе без рецир-куляции. Суть данного эксперимента сводилась к то-му, что производилась экстирпация матки с верхней третью влагалища.…”