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Obstetrics & Gynecology:
doi: 10.1097/01.AOG.0000230398.32794.9d
Original Research

Misoprostol Administered by Epithelial Routes: Drug Absorption and Uterine Response

Meckstroth, Karen R. MD, MPH1; Whitaker, Amy K. MD2; Bertisch, Suzanne MD3; Goldberg, Alisa B. MD, MPH4; Darney, Philip D. MD, MSc1

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Author Information

From the 1Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Francisco, San Francisco, California; 2Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Women's Hospital, University of Pittsburgh, Pittsburgh Pennsylvania; 3Division for Research and Education in Complementary and Integrative Medical Therapies, Harvard Medical School, Boston, Massachusetts; 4Obstetrics, Gynecology & Reproductive Biology, Harvard Medical School & Brigham and Women's Hospital and Planned Parenthood League of Massachusetts, Boston, Massachusetts.

Funded by the Bixby Center for Reproductive Health Research & Policy and the National Institute of Health through the San Francisco General Hospital General Clinical Research Center.

The authors thank Neal Benowitz, MD, Professor, Department of Clinical Pharmacy, University of California, San Francisco for assistance with pharmacokinetic analysis and Peter Bacchetti, PhD, Department of Epidemiology & Biostatics and Alan Bostrom for statistical analysis.

Corresponding author: Karen R. Meckstroth, MD, MPH, San Francisco General Hospital, Ward 6D, 1001 Potrero Avenue, San Francisco, CA 94110; e-mail: meckstrothk@obgyn.ucsf.edu

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Abstract

OBJECTIVE: To quantify and compare serum levels and uterine effects following vaginal (dry), vaginal (moistened), buccal, and rectal misoprostol administration.

METHODS: Forty women seeking elective abortion between 6 and 12 6/7 weeks were randomly assigned to receive 400 μg of misoprostol by one of four routes. A 2.5-mm pressure monitoring catheter was placed through the cervix to the uterine fundus to record uterine tone and activity during the 5-hour observation period. Serum levels of misoprostol acid were measured at 15 and 30 minutes, then every 30 minutes.

RESULTS: The four groups were similar in age, race or ethnicity, body mass index, parity, and gestation. Serum levels after vaginal, vaginal moistened and buccal administration rose gradually, peaked between 15 and 120 minutes and fell slowly. Vaginal and vaginal moistened routes produced higher peak serum levels than buccal and rectal (445.9 and 427.1 compared with 264.8 and 202.2 pg/mL; P=.03) and higher serum concentration area under the curve at 5 hours (1,025.0 and 1279.4 compared with 519.6 and 312.5 pg-hr/mL; P<.001). Uterine tone and activity, however, were similar for buccal and the two vaginal routes. After rectal administration, serum levels peaked earlier (P<.001) then dropped more abruptly, and peak uterine tone (P<.001) and total activity (P=.04) were lower than after the other routes.

CONCLUSION: Although serum levels were lower for buccal compared with the vaginal routes, the three routes produced similar uterine tone and activity. Rectal administration produced lower uterine tone and activity. Vaginal serum levels were two to three and a half times higher than those observed in prior misoprostol pharmacokinetic studies.

LEVEL OF EVIDENCE: II-1

The synthetic prostaglandin E1 misoprostol is used widely in early pregnancy to effect uterine tone, uterine contractions, or cervical softening. For reproductive indications, vaginal misoprostol is often favored over oral administration due to a lower incidence of adverse effects and improved uterine response.1,2 However, given the high variability of absorption and dissolution of misoprostol in the vagina, and many women's preference to avoid vaginal exams, investigators have evaluated alternative routes of epithelial absorption. Clinical trials of the sublingual and buccal routes have demonstrated efficacy for medical abortion3,4 and for cervical ripening before surgical abortion5–8 and labor induction.9–11 Sublingual misoprostol has also demonstrated efficacy for medical management of miscarriage12,13 and cervical priming in nonpregnant women.14 Rectal administration of misoprostol has been evaluated primarily for the prevention15 and treatment16 of postpartum hemorrhage and management of the third stage of labor, but is also used for postabortal hemorrhage. Other studies have investigated the pharmacokinetics of misoprostol administered by various routes; however, we identified only one prior study that evaluated both serum pharmacokinetics and uterine activity after vaginal and oral misoprostol in first trimester patients before suction curettage.17 Our study sought to evaluate the serum pharmacokinetics and uterine response for 5 hours after four routes of epithelial administration used commonly in women's reproductive healthcare.

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MATERIALS AND METHODS

We studied 40 healthy women with a singleton intrauterine pregnancy between 6 0/7 and 12 6/7 weeks of gestation who presented to San Francisco General Hospital's Women's Options Center requesting termination of pregnancy between April 2001 and February 2002. Gestational age was based on the woman's last menstrual period and confirmed by pelvic ultrasonography. Gestational age was changed if ultrasonography noted a difference of more than 5 days. All participants gave written informed consent in English or Spanish, and the study was approved by the University of California, San Francisco, Committee for Human Research and the San Francisco General Hospital General Clinical Research Center. All women were 18 years or older, had a body mass index (BMI) between 19.0 and 40 kg/m,2 and had signed informed consent for surgical termination of pregnancy. Women with significant cardiovascular or cerebrovascular disease, asthma requiring systemic steroids in the previous 2 months, active renal, liver, hematologic, or inflammatory bowel disease, uterine leiomyoma larger than 3 cm, evidence of spontaneous abortion, evidence of cervical infection, an intrauterine device in place, inadequate venous access, or known allergy to misoprostol were excluded from the study.

Participants did not eat or drink after midnight of the study day. Patients underwent a history and physical examination before beginning the study. A research physician then placed a 5-F intrauterine pressure transducer (2.5-mm Millar Microtip PD-771; Millar Instruments Inc., Houston, TX) through the cervical canal and advanced it extra-amniotically to the level of the uterine fundus under ultrasound guidance. The catheter was secured to the cervix with a single 4–0 polyglactin (Vicryl, Ethicon Endo-Surgery, Inc., Cincinnati, OH) suture. Before beginning the study, we tested catheter placement and uterine monitoring on two patients, who were also included in all institutional approvals. Women were then taken by wheelchair to the General Clinical Research Center where a research nurse placed an intravenous catheter suitable for multiple blood draws. Intravenous fluids were maintained at 100 mL per hour. The pressure transducer was then connected to a tc510 control unit (Fogg System Company, Inc., Aurora, CO) through a HP Series 50 XM uterine pressure monitor (Agilent Technologies, Palo Alto, CA). Patients remained in the supine position and continued fasting for the 5 hours of the study from this point onward.

The women were randomly assigned based on a random number table using blocks of six, to four groups of 10 participants each. A research assistant prepared numbered and sealed opaque envelopes indicating treatment allocation before beginning enrollment. A research assistant enrolled participants and opened the next consecutive envelope for group assignment. A research physician administered two 200-μg tablets (400 μg) of misoprostol (Cytotec, Pfizer, New York, NY) by the assigned route of administration: vaginal dry, vaginal moistened, buccal, or rectal. For women in the vaginal dry group, the investigator digitally placed the tablets in the posterior fornix of the vagina. The vaginal moistened group had 2 mL of normal saline dripped onto the tablets by syringe before similar placement. Women in the rectal group received the two tablets by digital rectal administration. All vaginal and rectal placements were done by a research physician, and no or minimal lubricant was used. Women in the buccal group were instructed to place one tablet between their teeth and buccal wall on each side of their mouths and to let both tablets dissolve without chewing or swallowing whole. If the tablets did not dissolve after 20 to 30 minutes, the participant was instructed to move the tablet a bit in the buccal compartment. With movement, the tablets dissolve promptly. Researchers and participants were not blinded to the route of administration.

A continuous uterine pressure tracing was obtained for at least 15 minutes before misoprostol administration and for the entire 5 hours after administration. The two patients who had a small amount of uterine activity after catheter placement were observed until the activity resolved before administering the misoprostol. Intrauterine tonus and uterine activity were recorded continuously, then were measured and calculated for 10-minute segments every 30 minutes by study personnel blinded to treatment group. Uterine tone is reported as the mean mm Hg difference for each 10-minute segment from premedication baseline tone. Alexandria Units18,19 are reported as the total measurement for all contractions for each 10-minute segment. Unlike Montevideo Units, Alexandria Units incorporate the duration of the uterine contraction and more closely approximate the area under the curve of the contraction, especially when the contraction duration varies, as we noted with pilot participants before this study and study participants. Like Montevideo units, Alexandria units do not incorporate the underlying uterine tone. We defined sustained uterine activity as Alexandria Units more than 300 lasting for at least three 10-minute data segments during the 5-hour observation period. We chose 300 Alexandria Units because that level corresponds approximately with 200 Montevideo Units, which is commonly used as a level of adequate uterine activity in labor.

Blood samples (10 mL) were obtained before misoprostol administration and at 15, 30, 60, 90, 120, and 300 minutes after administration. These sample times were determined from previous data describing vaginal misoprostol concentration over time, which showed peak levels between 60 and 120 minutes.20 Because an initial participant demonstrated a rapid and high peak blood level after rectal administration, a 5-minute blood drawing was added for that group. It was not included for all groups because of the high cost of the serum assay. Blood was immediately centrifuged and frozen below −20°C, as recommended by GD Searle and Co. (now Pfizer, New York, NY). Samples were shipped in a polystyrene cooler with dry ice by express courier to Anapharm Laboratories (Montreal, Quebec, Canada). Serum misoprostol acid concentration was measured at 15 and 30 minutes, then every 30 minutes by gas chromatography and electron-capture negative chemical ionization mass spectrometry, using 2H9-misoprostol as internal standard. Misoprostol acid and its internal standard were extracted from human heparinized plasma using 500 μL of plasma and C18 solid phase extraction cartridges. Compounds were eluted with methanol. Analysis was performed on an MDS SCIEX API 3000 tandem mass spectrometer using Turbo Ionspray interface. Negative ions were measured using MRM mode with m/z 367.3[white rightwards arrowhead with long tail]249.3 for misoprostol acid. The compounds were eluted from a Phenomenex Jupiter C18 column using methanol, ammonium formate 0.5 mm, and acetonitrile (65/30/5), as the mobile phase.

To monitor adverse effects, oral temperature was recorded every 30 minutes and participants were instructed to notify research staff or their nurse regarding uterine cramping, bleeding, nausea, vomiting, diarrhea, chills, and other symptoms. The occurrence of these prostaglandin-related adverse effects was recorded for each participant in case a large, detectable difference was observed. All adverse effects were treated with medications as needed. After completion of the study, the participants were taken back to the hospital clinic for their scheduled surgical abortion where the pressure catheter was removed.

Area under the serum misoprostol acid concentration-time curve (AUC) was calculated according to the trapezoidal method: Area under the curve (AUC)={½[Cx+Cx-1][Tx–Tx-1]}, from x=1 to n, where C=serum concentration, T=time, and n=number of serum concentration measurements. We calculated AUC at 30, 60, 90, 120, 150, 180, 210, 240, 270, and 300 minutes for all 40 participants. Our primary outcome measure was comparison of AUC (drug exposure) at 4 and 5 hours for the four routes. We evaluated results at 4 hours to compare with prior studies. Secondary outcomes included peak serum levels and time to peak serum levels, as well as time to onset and levels of uterine tone and uterine contractions. We also sought to evaluate the relationship between serum misoprostol levels and uterine response.

Using STATA 8 (StataCorp LP, College Station, TX) and SAS 9.1 (SAS Institute Inc., Cary, NC) statistical software packages, we used t tests and analysis of variance to test the statistical significance of differences between means. We performed logarithmic transformation for variables that were not normally distributed by the Shapiro-Wilk test. Where log transformation was not adequate, nonparametric Kruskal-Wallis comparisons were made. Correlations were determined using Pearson and Spearman Rank correlation coefficients where appropriate. Association between adverse effects and serum levels were evaluated with the Mann-Whitney U test. We used Kaplan-Meier life table analysis to evaluate the relationship between drug exposure and onset of uterine response. Ten participants per group was recommended by our pharmacology consultation for this comparative pharmacokinetic study. At that time, the only prior study that had measured misoprostol acid serum levels found the AUC240 for 400 μg of misoprostol administered vaginally to be 500 pg-hr/mL± 296,20 so 10 participants per group provided 80% power to detect a difference of 400 pg-hr/mL in AUC240 at a 5% level of significance.

All enrolled participants completed the study protocol. Due to technical problems, a few data points from the uterine pressure monitor were not readable. Two data points were interpolated from accurate information immediately before and after the missing information. Two participants, one in the vaginal moistened group and one in the rectal group, had several uterine pressure data points that could not be reliably determined and these participants were not included in relevant analyses. The analyses from which they were excluded are noted in the tables detailing uterine tone and activity.

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RESULTS

The four groups were similar with respect to age, race, body mass index, parity, gestational duration, number of prior pregnancies, spontaneous abortions, and elective abortions. Participants' BMI ranged from 19.1 to 39.9, with 25% of participants overweight or obese. The mean age was 24.7 years and group means (vaginal, vaginal moist, buccal, rectal) for participant characteristics were 26.8, 23.5, 24.1, and 24.5 years; mean body mass index was 27.2 m2/kg (27.9, 25.0, 26.6, and 29.6); mean parity was 1.5 (1.6, 1.0, 1.5, 1.8); and mean gestational duration was 68 days (63.1, 70.4, 68.6, 69.7). Just over one half (52.5%) of the participants were African American, 17.5% were Latina, 15% were white, 7.5% were Asian, and 7.5% were of mixed or other ethnicity. Twenty-five percent had had one or two prior miscarriages, and 65% had had at least one prior elective abortion.

The mean plasma concentrations of misoprostol acid after the four routes of administration are detailed in Table 1 and shown in graphical form in Figure 1. Serum levels after vaginal dry, vaginal moistened, and buccal administration rose gradually and fell slowly. All but two of these participants had peak serum levels between 15 and 120 minutes, and 77% between 30 and 90 minutes. Although the ranges were similar, the vaginal moistened group demonstrated less variability in peak serum level and time to peak level than the vaginal route. All participants who received vaginal moistened misoprostol except one experienced peak serum levels between 30 and 60 minutes. Serum misoprostol acid levels in the rectal group peaked earlier then declined more rapidly than the other three groups. All participants in the rectal group except one had peak levels at 15 minutes, significantly earlier than the other three groups, with rapid decline thereafter. By 30 minutes, serum levels were significantly higher for the two vaginal groups compared with the buccal and rectal groups. Area under the curve (AUC) of serum concentration across time was highest for the two vaginal groups, moderate for the buccal group and significantly lower for the rectal group. There were two outliers with unusually high peak serum levels, one each in the vaginal and the vaginal moistened groups. Outliers were defined by graphical inspection and comparison of z scores. There was no difference in significance of outcomes when the two outliers were excluded. The two outliers were within the middle quartiles for gestational age and BMI and we expect that these reflect population variation and would not be outliers in a large sample.

Fig. 1
Fig. 1
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Table 1
Table 1
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Figure 2 and Table 2 detail the uterine tone response to the four routes of misoprostol administration. Before misoprostol administration, the mean uterine tone was 15.3 mm Hg (±6.8 mm Hg). Two patients had a small amount of uterine activity after placement of the uterine pressure monitor, which resolved before administration of misoprostol. Eighty percent of participants experienced an increase in uterine tone by 40 minutes and 90% by 70 minutes. One participant in the buccal group and 2 in the rectal group did not experience an increase in tone until after 2 hours. One participant in the rectal group never experienced an increase in uterine tone.

Fig. 2
Fig. 2
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Table 2
Table 2
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Figure 3, Table 3, and Table 4 detail the uterine activity response as measured in Alexandria Units. Despite higher serum levels in the vaginal groups, participants in the vaginal dry, vaginal moistened, and buccal groups experienced similar uterine activity. All participants experienced uterine contractions at some time during the study period, although not all participants had sustained uterine activity. Eighty percent of participants in the vaginal dry and buccal arms, 90% in the vaginal moistened arm, and 40% in the rectal arm attained sustained uterine activity (P=.06). Of the participants who attained regular uterine activity, the activity became regular at a mean of 110 minutes with little variability between groups. We repeated these analyses using a cutoff of 500 Alexandria Units and obtained the same results, although only 30% of participants in the rectal arm attained this level of activity, which was significantly lower than the other three groups (P=.015). In most of the participants who developed sustained uterine activity, contractions increased progressively until the peak, but in some cases, peaks and lulls occurred in uterine activity. In most participants (9 of 10 for vaginal, buccal and rectal; 6 of 10 of vaginal moistened), uterine activity had begun to decline by 5 hours after misoprostol dosing.

Fig. 3
Fig. 3
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Table 3
Table 3
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Table 4
Table 4
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We also sought to evaluate the relationship between drug exposure and uterine response. Serum concentration and exposure (AUC) were highly correlated with uterine tone and activity. Uterine tone demonstrated the highest Spearman rs values with serum level and AUC in the first hour, ranging from 0.60 to 0.70. The initial increase in uterine tone was even more highly correlated (Spearman rs 0.87) with the serum level in the first 15 minutes when participants who received rectal misoprostol were excluded. At 150 minutes after misoprostol administration, uterine activity correlated with AUC and peak serum level with coefficients ranging from .41 to .61.

We were unable to identify a drug exposure threshold above which uterine activity was assured. Figure 4 demonstrates a Kaplan-Meier graph which plots the level of drug exposure (AUC) against the percentage of participants who attained sustained uterine activity at that level. Participants who received vaginal moistened misoprostol had a higher level of drug exposure when they achieved sustained uterine activity. These participants experienced a somewhat faster initial rise in serum levels, which results in higher AUC at all subsequent times. These higher initial levels did not lead to faster onset or more overall uterine activity. The other three groups were very similar in the amount of drug exposure at the time when sustained uterine activity began.

Fig. 4
Fig. 4
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We found no graphical or statistical correlation between BMI and serum or uterine response parameters and no difference in serum levels or outcomes between normal weight (BMI 19–24.9) and obese (BMI 30–40) women. We also found no correlation between gestation and uterine response in this range of 6 to 13 weeks gestation.

There were no significant differences in adverse effects between groups, but the study did not have adequate power to detect these differences. Of 40 participants, 33 (83%) participants experienced abdominal pain, and 26 (65%) received medication for pain. Six (15%) participants experienced uterine spotting and 2 (5%) experienced bleeding during the study period. Two participants passed the pregnancy into the vagina by the time of the uterine aspiration procedure, which was within an hour of the end of the study period. One woman experienced chills and one experienced a fever to 38.0C. Five women experienced nausea and two women vomited. We found no association with peak serum levels and adverse effects, except for abdominal pain (P=.30). Although the two outliers for peak serum level complained of abdominal pain, only one requested medication and neither experienced nausea, fever, or vaginal bleeding.

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DISCUSSION

This study provides several insights into the pharmacokinetic characteristics of misoprostol and how they translate to uterine effects in early pregnancy. Like other pharmacokinetic misoprostol studies, we found a high degree of variability in serum levels for all routes of administration. Of all four groups, buccal administration led to the lowest variability in drug exposure and peak levels, although the difference in variability was not statistically significant.

As would be expected from the general properties of oral mucosal absorption, the buccal route led to a serum concentration curve that is similar in shape to the curve associated with vaginal absorption and markedly different from that demonstrated after sublingual administration.21 The larger surface area and thicker epithelium of the buccal compartment is more similar to the vagina than the sublingual compartment, which is thin, vascular, and constantly bathed in saliva. In the only other report of pharmacokinetics from buccal administration,22 peak levels (229 pg/mL, range 140–1,160 pg/mL) were similar in magnitude but occurred earlier (30 minutes, 22.5–45 minutes) than in our study. This may be because Schaff et al22 instructed participants to remove the remaining pills after 30 minutes, rather than retain them until they were dissolved. Pills dissolve more rapidly in the sublingual compartment and sometimes take more than 30 minutes when administered buccally. Our AUC4 hours for buccal administration (475 pg/mL, range 114–1,064pg/mL) was similar to those published by Schaff et al (380 pg/mL, range 223–1,470 pg/mL).22

Although the shape of the misoprostol serum across time curves for vaginal absorption were similar to those published previously, our mean peak serum levels for the two vaginal routes averaged 2.7 (range 2.1–3.6) times higher than mean peak levels in all prior studies of pharmacokinetics after vaginal administration of 400 μg in early pregnancy. Prior studies found peak serum levels of 165 pg/mL,20 125 pg/mL,21 and 211 pg/mL23 with dry tablets and 163 pg/mL with moistened tablets.21 We propose that this may be due to the cervical cleaning before the placement of the uterine pressure catheter. Although only the cervix was swabbed with povidone-iodine (Betadine, Purdue Pharma L.P., Stamford, CT) dry gauze was used to remove liquid from the posterior fornix and vagina. This likely removed vaginal mucus and exposed the epithelium more directly to the misoprostol tablets. Although clinical studies of medical abortion have attempted this with vaginal douching,24 whether vaginal absorption and clinical effectiveness can be enhanced by first cleaning the cervix or vagina remains to be seen. Although assays run at different times or institutions could theoretically add variability, we feel this is an unlikely explanation for the difference in the two vaginal routes.

The serum concentration curve after rectal administration is similar in shape and magnitude to that noted after oral administration in other trials,17,20,21 with a rapid peak and decline of serum levels and a lower area under the curve. Our serum concentration graph for rectal absorption differs from that reported by Kahn et al,23 who noted a slower rise to peak levels, more similar in shape to vaginal administration. Chong et al,25 who investigated pharmacokinetics after rectal administration in postpartum women, also found a more gradual rise. In our study, all but one participant who received rectal misoprostol experienced peak serum levels at 15 minutes, with a rapid decline afterward. It is possible that this rapid dissolution and absorption occurred because we avoided touching the pills with lubricating gel during the examination.

Despite much higher serum levels after the vaginal administration, uterine activity after both vaginal routes and the buccal route were very similar. These uterine response results suggest that there is likely a threshold of serum level or drug exposure beyond which uterine tone and activity do not respond equally. An evaluation of uterine tone after term delivery also found that higher doses of oral misoprostol led to more adverse effects without achieving additional uterine activity.24 Increased uterine tone occurred reliably after all three routes and, beginning 1 to 2.5 hours after administration, uterine contractions increased until 4 or 5 hours after administration. Rather than demonstrating a more direct response from the buccal, vaginal, and rectal routes, this likely suggests that either duration of exposure contributes to the development of uterine activity or, regardless of exposure, it takes a minimal amount of time between the initiating agent and the development of sustained contractions. We found it very interesting that there was little variability in time to sustained contractions and that the three groups other than vaginal moistened exhibited a very similar relationship between level of drug exposure and sustained uterine activity (Fig. 4). In most participants, uterine activity had begun to decline by 5 hours, even though the pregnancy was still present in the uterus in all but 2 participants. The rectal route resulted in less uterine activity that did not reliably increase with time.

Depending on the clinical indication, different uterine responses are desired from misoprostol. In the case of postpartum or postabortion hemorrhage, a rapid rise in uterine tone may be more important than reliable onset of uterine contractions 30 to 90 minutes after administration. Clinical trials have suggested that rectal misoprostol is effective for the treatment of postpartum hemorrhage. It may be that the higher dose employed in most clinical studies (1,000 μg) produces a more reliable increase in uterine tone or that rectal absorption is more reliable after term delivery than in early pregnancy. For other indications, such as expulsion of a pregnancy, it is likely that sustained uterine contractions are required. Our study suggests that buccal administration offers an alternative that does not cause high peak levels yet produces a reliable uterine response, similar to vaginal administration. Buccal administration may have the additional advantage of decreased interindividual variability in uterine response. Like the sublingual route, buccal administration may be more acceptable to patients and clinicians compared with vaginal administration.

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© 2006 The American College of Obstetricians and Gynecologists

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