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    Mean plasma MFA concentration-versus-time curves for 8 healthy adult horses that received a single dose of misoprostol (5 μg/kg) administered PO when unfed and fed (circles and squares, respectively) and PR (no food restriction; rectangles) in a crossover study design. Concentrations were measured before (time 0) and at 5, 10, l5, 20, 30, 45, 60, 30, and 90 minutes and 2, 4, 8, l2, and 24 hours after drug administration; however, data are shown for the first 4 hours only because concentrations were below the LLOQ of the assay (100 pg/mL) at all subsequent measurement points when misoprostol was administered PO and after the 90-minute point when it was administered PR. Error bars represent SD.

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Single-dose pharmacokinetics of orally and rectally administered misoprostol in adult horses

Christine T. Lopp DVM1, Annette M. McCoy DVM, PhD1, Dawn Boothe DVM, PhD2, David J. Schaeffer PhD1, and Kara Lascola DVM, MS2
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  • 1 1Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802
  • | 2 2Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL 36849

Abstract

OBJECTIVE

To characterize the pharmacokinetics of a clinically relevant dose of misoprostol administered PO or per rectum (PR) to horses.

ANIMALS

8 healthy adult horses.

PROCEDURES

In a randomized 3-way crossover design, horses received a single dose of misoprostol (5 μg/kg) administered PO (with horses fed and unfed) and PR, with a minimum 3-week washout period separating the experimental conditions. Blood samples were obtained before and at various points after drug administration (total, 24 hours), and plasma concentrations of misoprostol free acid were measured.

RESULTS

Mean maximum plasma concentration of misoprostol was significantly higher in the PR condition (mean ± SD, 967 ± 492 pg/mL) and unfed PO condition (655 ± 259 pg/mL) than in the fed PO condition (352 ± 109 pg/mL). Mean area under the concentration-versus-time curve was significantly lower in the PR condition (219 ± 131 pg•h/mL) than in the unfed (1,072 ± 360 pg•h/mL) and fed (518 ± 301 pg•h/mL) PO conditions. Mean time to maximum concentration was ≤ 30 minutes for all conditions. Mean disappearance half-life was shortest in the PR condition (21 ± 29 minutes), compared with values for the unfed (170 ± 129 minutes) and fed (119 ± 51 minutes) PO conditions. No adverse effects were noted.

CONCLUSIONS AND CLINICAL RELEVANCE

Misoprostol was rapidly absorbed and eliminated regardless of whether administered PO or PR to horses. Rectal administration may be a viable alternative for horses that cannot receive misoprostol PO, but this route may require more frequent administration to maintain therapeutic drug concentrations.

Abstract

OBJECTIVE

To characterize the pharmacokinetics of a clinically relevant dose of misoprostol administered PO or per rectum (PR) to horses.

ANIMALS

8 healthy adult horses.

PROCEDURES

In a randomized 3-way crossover design, horses received a single dose of misoprostol (5 μg/kg) administered PO (with horses fed and unfed) and PR, with a minimum 3-week washout period separating the experimental conditions. Blood samples were obtained before and at various points after drug administration (total, 24 hours), and plasma concentrations of misoprostol free acid were measured.

RESULTS

Mean maximum plasma concentration of misoprostol was significantly higher in the PR condition (mean ± SD, 967 ± 492 pg/mL) and unfed PO condition (655 ± 259 pg/mL) than in the fed PO condition (352 ± 109 pg/mL). Mean area under the concentration-versus-time curve was significantly lower in the PR condition (219 ± 131 pg•h/mL) than in the unfed (1,072 ± 360 pg•h/mL) and fed (518 ± 301 pg•h/mL) PO conditions. Mean time to maximum concentration was ≤ 30 minutes for all conditions. Mean disappearance half-life was shortest in the PR condition (21 ± 29 minutes), compared with values for the unfed (170 ± 129 minutes) and fed (119 ± 51 minutes) PO conditions. No adverse effects were noted.

CONCLUSIONS AND CLINICAL RELEVANCE

Misoprostol was rapidly absorbed and eliminated regardless of whether administered PO or PR to horses. Rectal administration may be a viable alternative for horses that cannot receive misoprostol PO, but this route may require more frequent administration to maintain therapeutic drug concentrations.

Prolonged or inappropriate administration of NSAIDs has been associated with the development of ulcerative colitis in adult horses, and evidence suggests that an NSAID-mediated delay in intestinal healing is a potential concern in horses with mucosal damage, such as those that have undergone surgery to treat colic.1,2 In addition, NSAID administration may contribute to development of equine gastric glandular disease in some horses.3 Given the widespread administration of NSAIDs to adult horses for the treatment of various conditions, including colic and musculoskeletal problems, research is warranted into drugs that can mitigate these deleterious adverse effects. Misoprostol, a synthetic, stable methyl ester analog of prostaglandin E1 and an agonist of prostanoid receptor subtypes E2, E3, and E4, is FDA approved for use in humans for the prevention of NSAID-related gastric and duodenal injury4 and therefore represents one such medication.

In adult horses, misoprostol has been recommended for the treatment of NSAID-induced ulcerative colitis.5 In ponies, synthetic prostaglandin E2 was shown to prevent ulceration of the gastrointestinal tract after experimental induction of phenylbutazone toxicosis.6 More recently, horses with equine gastric glandular disease had superior resolution of ulcers after 28 days of receiving misoprostol (5 μg/kg, PO, q 12 h), compared with horses that received omeprazole and sucralfate.7 Furthermore, experimental evidence suggests that misoprostol may hasten repair of ischemic damaged mucosa.2 Numerous in vitro and ex vivo studies8–17 in humans and other species, including horses, have also shown the potential anti-inflammatory effects of misoprostol through cAMP-mediated pathways.

Despite these potential advantages, the clinical use of misoprostol in horses has been limited, owing in part to the lack of information about the pharmacokinetics of the drug in this species. The pharmacokinetics have been reported of a single dose of misoprostol administered PO to unfed horses.10 However, for many horses, routine PO administration of medications following food withholding is difficult and, in the authors’ opinion, should be limited to situations where evidence supports this mode of administration. Nevertheless, significant reductions in bioavailability have been reported for several drugs when administered to fed horses.18–27 Furthermore, there are scenarios when alternative routes of administration, such as PR, would be clinically useful, particularly for horses in which PO drug administration may be contraindicated or challenging owing to behavioral or medical reasons. To the authors’ knowledge, neither the effects of feed on the pharmacokinetics of misoprostol administered PO nor the pharmacokinetics of misoprostol administered PR have been described in adult horses.

The objective of the study reported here was to characterize the pharmacokinetics of a single dose of misoprostol administered to adult horses via 2 clinically relevant routes of administration: PO (with and without feed) and PR. We hypothesized that the Cmax would be significantly greater when horses were unfed (vs fed) before misoprostol was administered PO or when the drug was administered PR, the tmax would be significantly shorter when misoprostol was administered PO versus PR, and the AUC would be significantly smaller when misoprostol was administered PO versus PR.

Materials and Methods

Animals

Eight university-owned healthy adult (age range, 8 to 22 years) horses of various breeds (1 stallion, 2 geldings, and 5 nonpregnant mares), ranging in body weight from 450 to 701 kg, were used for the study. All horses were deemed healthy on the basis of physical examination findings. Horses were housed individually for a minimum of 24 hours prior to and for the duration of each experimental condition and had free access to water. Unless the experimental condition required otherwise, horses were fed mixed grass hay (2 flakes twice daily; approx 2 kg/flake). No concentrates were fed at any point during the study or washout periods.

Horses were housed on pasture during washout periods in accordance with the standard protocol for university-owned horses. Horses were monitored continuously for the first 2 hours and then hourly during experimental conditions for signs of abdominal discomfort and changes in fecal consistency. Physical examinations were performed prior to and then every 12 hours until 24 hours after completion of each experimental condition. All procedures were reviewed and approved by the University of Illinois Institutional Animal Care and Use Committee (protocol No. 17212).

Experimental design

A 3-way randomized crossover design was used, with a minimum 3-week washout period between experimental conditions. Treatment order was assigned by simple randomization. Prior to each experimental condition, horses were instrumented with a 14-gauge over-the-needle cathetera placed in a jugular vein to facilitate repeated blood sample collection. A single dose of misoprostolb (5 μg/kg) was administered PO after the horses had or had no access to mixed grass hay (unfed and fed PO conditions) or PR (no food restriction). In the unfed PO condition, hay was withheld from horses for 12 hours prior to drug administration and for 2 hours after drug administration. In the fed PO condition, horses were offered 2 flakes of hay as previously described, were observed to eat 20 minutes prior to drug administration, and were allowed to continue eating after drug administration. Horses in the PR condition were maintained on the previously described feeding protocol.

For PO administration to unfed and fed horses, the calculated amount of misoprostol tablets (100 μg) that would provide a dose of 5 μg/kg was dissolved in 30 mL of water and administered via an oral syringe. After drug administration, 20 to 30 mL of water was drawn up into the syringe and administered PO to ensure complete delivery of the drug. For PR administration, manure was manually evacuated from the rectum prior to drug administration. Misoprostol tablets were dissolved in 30 mL of water and infused into the rectum via a 41-cm 8F red rubber catheter inserted to the same length (41 cm) in each horse. After PR drug administration, an additional 30 mL of water was administered via the catheter to ensure delivery of the entire dose.

Sample collection

Prior to collection of each blood sample, 10 mL of blood was drawn from the jugular catheter and discarded to clear the catheter and extension line. Blood samples were then collected immediately before drug administration (0 hours) and then at 5, 10, 15, 20, 30, 45, 60, and 90 minutes and 2, 4, 8, 12, and 24 hours after drug administration. Samples were immediately transferred to tubes containing sodium heparin, placed on ice, and then centrifuged (400 × g for 10 minutes at 4°C) within 15 minutes after collection. The plasma was separated and transferred to 2-mL vials, flash frozen in liquid nitrogen, and stored at −80°C until analysis.

Measurement of plasma MFA concentration

Misoprostol undergoes rapid de-esterification into a free acid form4,17; consequently, plasma concentrations of the free acid form are measured in pharmacokinetic analyses of the drug. Plasma MFA concentration was measured via LC-MS-MS with a triple quadropole systemc and softwared designed for data acquisition and analysis.

For the LC-MS-MS assay, a 50-μL aliquot of each plasma sample was thawed, mixed with 100 μL of acetonitrile and spiked with 5 μL of d5-misoprostol acid,e vortex mixed, and centrifuged. The supernatant was collected for LC-MS-MS instrument injection. Liquid chromatography separation was performed on a C18 columnf (2.1 × 100 mm; 1.5-μm particle size) with mobile phase A (0.1% formic acid in water) and mobile phase B (0.1% formic acid in acetonitrile) and a flow rate of 0.3 mL/min. The linear gradient was as follows: 0 to 0.5 minutes, 25% of B; 1 to 2.5 minutes, 100% of B; and 3 to 4.5 minutes, 25% of B. The autosampler was set at 10°C with an injection volume of 5 μL. Mass spectra were acquired under negative electrospray ionization with the following settings: ion spray voltage, −2,500 V; sheath gas, −40; auxiliary gas, −6; sweep gas, −1; ion transfer tube, −335°C; and vaporizer, −260°C. Multiple reaction monitoring was used for quantification (MFA, m/z 367.1 → m/z 249.0; internal standard MFA-d5, m/z 372.2 → m/z 249.1).

Prior to sample analysis, drug-free equine plasma aliquots were used for generation of standard calibration curves, with commercially available MFAe and MFA-d5e used as the internal standard. The calibration concentration range was 100 to 5,000 pg/mL, and the coefficient of determination (R2) was ≥ 0.993 for all curves. The LLOQ was 100 pg/mL. At plasma concentrations of 0.3, 1, and 3 ng of misoprostol/mL, mean ± SD percentage recovery was 66.7 ± 9.1%, 71.0 ± 6.2%, and 72.8 ± 3.3%, respectively. For misoprostol detection in plasma, mean ± SD observed within-run accuracy ranged from 96.1 ± 8.2% to 116.2 ± 3.4% and within-run precision ranged from 4.3% to 7.8%. For between-run accuracy and precision, mean ± SD accuracy ranged from 98.9 ± 7.4% to 101.3 ± 4.1% and precision ranged from 3.7% to 5.4%.

Pharmacokinetic analysis

Plasma MFA concentrations lower than the LLOQ of the assay are not reported and were treated as 0 pg/mL for purposes of pharmacokinetic and statistical analysis. Plasma MFA concentration-versus-time data were subjected to noncompartmental analysis by use of computer software.g The AUC0-∞ and AUCall were calculated with the log-linear trapezoidal method. The identified Cmax and last measured plasma concentration along with the corresponding times at which they were observed (tmax and tlast) were directly calculated. The slope of the terminal component of the drug-elimination time curve was determined by nonlinear regression. Without IV drug administration having been performed, the terminal component could not be confirmed to be elimination and therefore both the elimination rate constant and half-life are reported as disappearance values (1/λ and t1/2dis, respectively); t1/2dis is reported as harmonic mean ± pseudoSD. Values for Cl and Vd were uncorrected for bioavailability and thus are reported as Vd/F or Cl/F. Additional evaluated parameters included mean plasma concentration during the study period, MRT, percentage of the AUC0-∞ extrapolated from the terminal component of the curve, and relative bioavailability for each route combination (AUCroute1/AUCroute2).

Statistical analysis

The Shapiro-Wilk and Kolmogorov-Smirnov tests were used to evaluate the data distribution for each evaluated parameter by use of statistical software.h Although data for a few parameters were not normally distributed, all values are reported as mean ± SD (range) to facilitate comparisons. The CV for selected values was calculated as the SD divided by the mean. For comparisons of each pharmacokinetic value among the 3 experimental conditions, data were logarithmically transformed and linear mixed-effects modeling with Tukey-Kramer adjustment was performed to account for the repeated measurements per horse (unstructured covariance matrix). Values of P < 0.05 were considered significant.

Results

Animals

All 8 horses completed each experimental condition and appeared to tolerate PO (regardless of whether unfed or fed) and PR administration of misoprostol. The stallion and 1 of the 2 geldings resisted manual evacuation of manure; however, misoprostol was administered PR as otherwise described. No adverse signs consistent with abdominal discomfort or changes in manure consistency were evident during the follow-up period after drug administration, and physical examination findings were unremarkable throughout and between all examination periods.

Misoprostol free acid was detected in plasma samples from all horses in all experimental conditions at 5 minutes after misoprostol administration. Plasma concentrations were below the LLOQ (100 pg/mL) by 90 minutes after misoprostol administration for all horses in the PR condition and by 8 hours for all horses during the unfed and fed PO conditions (Table 1). Plasma concentration-versus-time curves were generated for each experimental condition (Figure 1). Mean ± SD percentage of the AUC0-∞ that was extrapolated was 48 ± 17% for the unfed PO condition, 57 ± 6% for the fed PO condition, and 37 ± 4% for the PR condition (values not statistically compared).

Table 1—

Mean ± SD plasma MFA concentrations* (number of horses with measurements) at various points after 8 healthy adult horses received a single dose of misoprostol (5 μg/kg) administered PO when unfed and fed and PR (no food restriction) in a crossover study design.

TimeUnfed POFed POPR
5 min431 ± 220 (8)259 ± 83 (8)967 ± 492 (8)
30 min545 ± 226 (8)283 ± 100 (8)203 ± 50 (6)
1 h346 ± 102 (8)276 ± 101 (7)188 ± 1 (2)
90 min276 ± 90 (8)243 ± 61 (6)ND
2 h264 ± 96 (8)237 ± 54 (4)ND
4 h179 ± 28 (6)208 ± 13 (2)ND

ND = Not determined because values for all 8 horses were below the LLOQ (100 pg/mL).

By the 8-hour measurement point, all 8 horses had values below the LLOQ.

Figure 1—
Figure 1—

Mean plasma MFA concentration-versus-time curves for 8 healthy adult horses that received a single dose of misoprostol (5 μg/kg) administered PO when unfed and fed (circles and squares, respectively) and PR (no food restriction; rectangles) in a crossover study design. Concentrations were measured before (time 0) and at 5, 10, l5, 20, 30, 45, 60, 30, and 90 minutes and 2, 4, 8, l2, and 24 hours after drug administration; however, data are shown for the first 4 hours only because concentrations were below the LLOQ of the assay (100 pg/mL) at all subsequent measurement points when misoprostol was administered PO and after the 90-minute point when it was administered PR. Error bars represent SD.

Citation: American Journal of Veterinary Research 80, 11; 10.2460/ajvr.80.11.1026

Several significant differences in other pharmacokinetic values were identified among experimental conditions (Table 2). The Cmax for misoprostol was significantly greater for the unfed PO (P = 0.008) and PR (P = 0.01) conditions than for the fed PO condition, whereas tmax was significantly shorter for the PR condition than for the unfed PO (P = 0.005) and fed PO (P = 0.002) conditions. Respective CVs for Cmax in the unfed PO, fed PO, and PR conditions were 39%, 31%, and 51% and for tmax were 63%, 99%, and 0%.

Table 2—

Pharmacokinetic values for misoprostol following administration to the horses of Table 1.

ParameterUnfed POFed POPR
Cmax (pg/mL)655 ± 259a (420–1,124)352 ± 109b (234–596)967 ± 492a (352–1,803)
tmax (min)21 ± 13a (10–45)30 ± 29a (5–90)5 ± 0b*
Clast (pg/mL)199 ± 44 (144–262)236 ± 59 (151–319)194 ± 53 (130–280)
tlast (min)210 ± 56a (120–240)128 ± 73a (45–240)46 ± 22b (15–75)
AUC0-∞ (pg•h/mL)2,217 ± 955a (1,221–4,317)1,358 ± 891b (536–2,727)385 ± 153c(196–605)
AUCall (pg•h/mL)1,072 ± 360a (549–1,502)518 ± 301b (177–980)219 ± 13c (116–163)
I/λ (min−1)0.003 ± 0.0030.005 ± 0.0040.022 ± 0.011
t1/2dis (min)170 ± 129a (69–233)119 ± 51a (79–334)21 ± 29b (6–53)
Cmean (pg/mL)86 ± 27a (49–136)55 ± 34b (22–106)16 ± 6c (8–25)
MRT (min)350 ± 269a (104–986)233 ± 165a (118–520)48 ± 46b (10–92)
Vd/F (mL/kg)13 ± 7a15 ± 4a11 ± 6a
Cl/F (mL/h/kg)2.4 ± 1.2a5.4 ± 3.0a18.0 ± 6.0b

Values are reported as mean ± SD (range) for all parameters except t1/2dis, which is reported as harmonic mean ± pseudoSD (range), and I/λ, Vd/F, and Cl/F, which are reported as mean ± SD only.

Clast = Last measured plasma concentration. Cmean = Mean plasma concentration during the study period.

No range is reported because all measured values were the same (5 minutes).

Within a row, values with different superscript letters differ significantly (P < 0.05).

The AUC0-∞ and AUCall for misoprostol were significantly (P < 0.02 for both comparisons) lower for the PR condition than for the unfed and fed PO conditions. These values also differed significantly (P < 0.05 for both comparisons) between the unfed and fed PO conditions. Respective CVs for the unfed PO, fed PO, and PR conditions were 43%, 65%, and 39% for AUC0-∞ and 34%, 58%, and 48% for AUCall.

Mean relative bioavailability of misoprostol in the PR condition was 20 ± 12% (range, 10% to 45%), compared with bioavailability in the unfed PO condition and 39 ± 28% (range, 13% to 82%), compared with bioavailability in the fed PO condition. Mean relative bioavailability of misoprostol in the fed PO condition was 48 ± 9% (range, 39% to 55%), compared with bioavailability in the unfed PO condition. Both t1/2dis and MRT were significantly (P ≤ 0.03 for all comparisons) shorter in the PR condition than in the unfed and fed PO conditions.

Discussion

In the present study, the pharmacokinetics of misoprostol were evaluated in horses under 3 experimental conditions: PO with hay withheld (unfed) and with access to hay when the drug was administered (fed) and PR with access to hay when the drug was administered. To our knowledge, this study represented the first of its kind. For horses that received the drug PO, relative bioavailability and Cmax were superior when misoprostol was administered with hay withheld, suggesting that feed adversely impacted absorption of this drug. Per rectum administration of misoprostol resulted in a different drug disposition profile than observed in the PO conditions. Contrary to our hypotheses, PR administration resulted in the highest Cmax and shortest tmax and t1/2dis. Drug exposure (area under the curve) with PR administration was lower than with both PO conditions, corresponding to inferior relative bioavailability.

The pharmacokinetics of misoprostol have been well described in humans for various routes of administration, including PO, buccal, sublingual, transrectal, and transvaginal.28–33 Misoprostol is approved in several countries for the prevention of NSAID-related gastric and duodenal injury in humans but is commonly used in an extralabel manner for obstetric purposes.4,17,30,33 The typical daily dose range is 400 to 800 μg. Although much higher doses have been reported for obstetric purposes,31 most reports describe the pharmacokinetics of a single 400-μg (5.5− to 8.8−μg/kg) dose administered via any route. Little information exists regarding therapeutic plasma concentrations.

In the present study, the tmax for the unfed and fed PO conditions was comparable to that reported for humans (12 to 30 minutes when fasted).4,28,29,34 The tmax values were also similar to the tmax (mean ± SD, 23 ± 2 minutes) reported for misoprostol administered PO to unfed horses in a previous study.10 In that study,10 the mean Cmax was 290 pg/mL, which is comparable to values reported for fasted humans.30,31 This mean Cmax more closely approximates the mean Cmax obtained for horses in the fed PO condition of the present study (352 pg/mL) and represents approximately 44% and 30% of the mean Cmax obtained for horses in the unfed PO and PR conditions, respectively.

In addition to Cmax, mean values for AUC0-∞ and t1/2dis for horses in the unfed PO condition in the study reported here were greater than those in the previous study10 (AUC0–00, 400 pg•h/mL; t1/2dis, 40 minutes). Comparisons of AUC0-∞ and t1/2dis between studies must be made cautiously. For all experimental conditions in the present study, > 25% of the AUC0-∞ was extrapolated from the concentration-versus-time curve, suggesting inaccuracy in determination of the terminal component of the curve. Inaccuracy in the terminal component directly affects values for t1/2dis and AUC0-∞ because both are derived from this parameter. The AUCall is not dependent on the terminal component and was, therefore, also reported and used for comparisons between experimental conditions in our study. Additional blood sample collection points may have improved the accuracy in defining the terminal component but may not have been useful for our study. The sample collection points used were identical to those in the previous study,10 which indicated that plasma MFA concentrations at 4 hours after drug administration fell below their LLOQ of 50 pg/mL for all but 1 horse. The higher LLOQ (100 pg/mL) in the present study, coupled with variability in the absorption and disappearance of misoprostol in all experimental conditions, decreased the number of quantifiable concentrations in the terminal phase and thereby increased the extent of extrapolation for the AUC0-∞.

The observed differences in detected plasma concentrations between the present study and the previous study10 may have reflected variability in misoprostol absorption as well as physiologic differences among horse populations or experimental protocols. Variability in absorption of misoprostol in humans is well recognized, with reported CVs for peak concentrations ranging from 30% to 75%, depending on the study and the route of administration. Some of the greatest variability has been reported for PR administration (73%),28 whereas the reported variability for PO administration is closer to 50% to 60%.29,35 Variability in absorption in the study reported here was comparable to these previously reported values, at 51% for the PR condition, 39% for the unfed PO condition, and 31% for the fed PO condition.

In humans, findings regarding the effect of food on misoprostol absorption are conflicting. Earlier evidence indicates that food reduces the rate but not the extent of misoprostol absorption,4 whereas more recent evidence suggests that food reduces both Cmax and bioavailability, particularly high-fat food.36,37 In the present study, the relative bioavailability of misoprostol in horses in the fed PO condition was 48% of that in the unfed PO condition, and this reduced bioavailability was reflected in a lower Cmax, AUC0-∞, and AUCall. The effect of feeding on oral bioavailability in horses is well recognized. In adult horses, administration of medications as topdressings or in the presence of feed within the stomach can alter both the rate and extent of drug absorption.18–27 The mechanisms behind this can include drug binding to ingesta, delays in gastric emptying, or ingesta forming a physical barrier to drug absorption.38,39 In addition, the method of administration, type of diet, and feeding schedule can all influence absorption of medications administered PO.23,39

No significant difference in tmax was identified between the unfed and fed PO conditions for horses in the present study. Although this finding suggested that with the feeding protocol used, the extent rather than the rate of oral drug absorption was primarily affected by feeding, there was also greater variability in the rate of absorption in the fed PO condition. The range and CV for tmax were 5 to 90 minutes and 99%, respectively, for the fed PO condition, compared with 10 to 45 minutes and 63% for the unfed PO condition. Notwithstanding lower absorption and relative bioavailability in the fed versus unfed PO condition, drug absorption and exposure were comparable to values reported for humans and unfed horses.10,30,32 Only the effect of hay on drug absorption under a single feeding protocol was investigated in the present study, and it remains unknown how modifications in diet, such as addition of concentrates, or in feeding regimen, such as provision of hay ad libitum, would change the pharmacokinetics of misoprostol when administered PO to horses.

In humans, transrectal administration of misoprostol results in a greater tmax (40 to 70 minutes) and lower achievable plasma concentration (80 to 200 pg/mL) and drug exposure, compared with oral and transvaginal administration.28,30,31 In the present study, the absorption and disappearance (elimination) of misoprostol administered PR to horses appeared similar to data reported for sublingual administration in humans,29,30,33,40 with the fastest absorption times and highest plasma concentrations of misoprostol observed after PR administration. Drug disappearance half-life and tlast were shorter, Cl/F was faster, and overall drug exposure (AUCall and AUC0-∞) was much lower with PR versus PO administration in the study reported here (Table 2). These differences suggested more rapid drug absorption and elimination by the PR route in horses.

Drugs administered PR may bypass first-pass metabolism by avoiding absorption into the portal circulation.41–43 This is particularly true for lipophilic drugs but is also dependent on how far caudally the drug is deposited within the rectum.42,43 In the present study, PR deposition of misoprostol was standardized across horses, but the physiology of PR drug absorption is less clearly defined for horses than for other species.42 It is also unknown how gastrointestinal inflammation may affect the kinetics of PR drug absorption. Our data suggested that in clinical situations, use of the PR route for horses may require more frequent dose administration than the PO route to maintain therapeutic drug concentrations. It is possible that dosing intervals for PR administration may be as frequent as every 3 to 6 hours, depending on the clinical reason for drug administration.

In the present study, variability in drug absorption was greatest in the PR condition, with a CV of 51% versus 39% and 31% in the unfed and fed PO conditions, respectively. Maximum plasma concentrations in the PR condition ranged from 352 to 1,803 pg/mL. Although these findings may have reflected normal variability in drug absorption, the 2 lowest Cmax values (352 and 392 pg/mL) were obtained for the 2 horses that would not allow manual evacuation of manure from the rectum. With these 2 horses removed from statistical analysis, the range in Cmax and the CV were 815 to 1,803 pg/mL and 33%, and a similar reduction in variability was achieved for AUC0-∞ and AUCall. The presence of fecal matter can interfere with absorption through inactivation of drugs such as antimicrobials, binding of drugs, or creation of a physical barrier to drug absorption.41,44

The present study had several limitations that warrant consideration. Although clinically relevant pharmacokinetic differences were identified among experimental conditions, suggesting the presence of important influences related to route of misoprostol administration, the number of included horses was small and there was a considerable amount of variability among horses in each experimental condition. Although fed horses were all observed to consume hay throughout the 20-minute period prior to drug administration, the amount of hay consumed during this period was not quantified and most likely differed among horses, thereby contributing to variability in drug absorption in the fed PO condition. Drug loss during administration could have contributed to the observed variability in drug absorption between PO conditions. Quantification of the volume of drug lost was not performed but was estimated to be minimal on the basis of informal observation. Direct administration of misoprostol to the stomach via nasogastric tube instead of via syringe may have reduced some of that variability but was not performed because we believed this did not represent a clinically relevant method of administration. Inclusion of IV misoprostol administration could have allowed for a more complete description of relative bioavailability for experimental condition but was also not included because of recognized safety concerns.45

Adverse effects of misoprostol administration in humans are dose dependent and most commonly include diarrhea and abdominal pain, but may also include nausea, vomiting, chills, shivering, and fever.11,36,46 Routes of administration that provide a gradual increase in or lower overall Cmax have been associated with fewer to no adverse effects.47 In horses, reported adverse effects include signs of abdominal discomfort and diarrhea.7,10 In 2 studies7,48 in which horses received misoprostol at a dosage of 5 μg/kg, PO, twice daily for up to 28 days, no adverse effects were reported, whereas occasional adverse effects (mild abdominal discomfort and soft manure) were noted in another study10 involving a single dose of misoprostol administered PO. In the present study, no adverse signs consistent with abdominal discomfort or changes in manure consistency were noted among horses in any experimental condition, regardless of plasma MFA concentration or rate at which the highest concentrations were achieved. Whether adverse effects would be more common in horses with concurrent gastrointestinal disease is unknown.

Current recommendations for administration of misoprostol to horses are based on information extrapolated from the human literature, and information on repeated dose administration to horses is limited to a report7 describing misoprostol administration at 5 μg/kg, PO, every 12 hours for the treatment of equine gastric glandular disease.7 No studies have been performed to evaluate the pharmacodynamics of misoprostol in horses, to the authors’ knowledge, and thus effective doses and dosing regimens have not been clearly defined. This is particularly true for the potential use of misoprostol for colonic or gastric mucosal healing3,5,49–52 or for mitigation of systemic inflammation.8–10 Given the results from the present study and a previous study10 of PO administration of misoprostol to horses, it is unlikely that evaluation of higher doses would be necessary, particularly because of the increased potential for development of adverse effects at higher doses. However, additional investigation is needed regarding the pharmacokinetics and pharmacodynamics of misoprostol with respect to repeated dose administration and different dosing intervals to better define the optimal dose, dosing interval, and route of administration required to maintain therapeutic plasma concentrations while minimizing potential adverse effects in horses.

Acknowledgments

Funded by the Companion Animal Memorial Fund of the University of Illinois.

The authors declare that there were no conflicts of interest.

ABBREVIATIONS

1/λ

Disappearance rate constant

AUC0-∞

Area under the concentration-versus-time curve from time 0 to infinity

AUCall

Area under the concentration-versus-time curve determined from all measurement points

Cl/F

Clearance corrected for bioavailability

Cmax

Maximum plasma concentration

CV

Coefficient of variation

LC-MS-MS

Liquid chromatographytandem mass spectrometry

LLOQ

Lower limit of quantification

MFA

Misoprostol free acid

MRT

Mean residence time

PR

Per rectum

t1/2dis

Half-life for drug disappearance

tlast

Time to last measured plasma concentration

tmax

Time to maximum concentration

Vd/F

Volume of distribution corrected for bioavailability

Footnotes

a.

Mila International Inc, Erlanger, Ky.

b.

Novel Laboratories Inc, Somerset, NJ.

c.

TSQ Altis, Thermo Fisher Scientific, Waltham, Mass.

d.

TraceFinder, version 4.1. Thermo Fisher Scientific, Waltham, Mass.

e.

Cayman Chemical, Ann Arbor, Mich.

f.

Accucore Vanquish C18+ column, Thermo Fisher Scientific, Waltham, Mass.

g.

Phoenix WinNonLin, version 8.1, Cetara, St Louis, Mo.

h.

SAS, version 9.4, SAS Institute Inc, Cary, NC.

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Contributor Notes

Dr. Lopp's present address is Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762.

Address correspondence to Dr. Lascola (km10068@auburn.edu).