Hypoluteoidism in the bitch is described as a reproductive condition in which insufficient levels of endogenous progesterone are present resulting in failure to maintain a functional secretory endometrium. This condition can prevent normal embryo implantation, development, and ultimately end in pregnancy loss. Hypoluteoidism in the bitch is a rising concern in small animal theriogenology and current medical therapies available to veterinarians are limited. The aim of this study was to determine the pharmacokinetics (PK) of intravaginally (Crinone®, Serono Laboratories, Norwell, MA) and orally delivered micronized progesterone (Prometrium®, Solvay Pharmaceuticals, Inc., Marietta, GA) in the bitch. We hypothesized that both vaginal and oral treatments would result in a dose-dependent increase in concentrations of plasma progesterone. We further hypothesized that oral dosing of micronized progesterone would result in greater, sustained plasma progesterone than those recorded in bitches treated with intravaginal (IVa) micronized progesterone gel. Eight adult sexually intact bitches in anestrus were arranged in a 4x4 Latin square cross over experimental design. Each subject rotated through four different progesterone treatment groups with a minimum seven day-wash out period between treatments: 100 mg oral micronized progesterone, 200 mg oral micronized progesterone, 45 mg intravaginal micronized progesterone and 90 mg intravaginal micronized progesterone. Blood samples from each subject were obtained at time points 0, 0.5, 2, 1.5, 2, 4, 6, 8, 12, 24, 36, 48 and 72 hours following one initial dosing of each treatment. Concentrations of plasma progesterone were determined by RIA (ImmuChem Double Antibody, 125I RIA Kit, MP Biomedicals, Costa Mesa, CA). Pharmacokinetic analysis was carried out using commercially available software (Phoenix WinNonlin 6.4, Certara Inc., Princeton, NJ). One-compartmental (intravaginal) and non-compartmental (oral administration) modeling were performed to analyze data using the mean concentrations for each dosing to calculate the area under the curve (AUC), maximum plasma concentration (Cmax), time elapsed to reach Cmax (Tmax), and elimination half-life ( t1/2).
Results for the 100 mg and 200 mg oral doses and 45 mg and 90 mg IVA doses were as follows: AUC, 30.86, 187.96, 90.64, and 226.68 ng.h.mL-1, respectively; Cmax, 13.47, 169, 8.68, and 13.24 ng.mL-1, respectively; Tmax, 0.5, 0.5, 0.84, and 1.67 hr, respectively, and half-life, 5.87, 6.76, 6.6, and 10.65 hr, respectively.
Micronized progesterone was readily absorbed in bitches when administered either orally or intravaginally. Contrary to our initial hypothesis, micronized progesterone exposure over time, as indicated by the area under the curve, was greater when intravaginal micronized progesterone was used. The ability of intravaginal preparations of micronized progesterone to induce sustained progesterone exposure may provide an alternative strategy for treating pregnant dogs whenever hypoluteoidism is being suspected.
| Identifer | oai:union.ndltd.org:LSU/oai:etd.lsu.edu:etd-07092017-013450 |
| Date | 17 July 2017 |
| Creators | Malbrue, Raphael Anthony |
| Contributors | Pinto, Carlos, Stout, Rhett, Langohr, Ingeborg |
| Publisher | LSU |
| Source Sets | Louisiana State University |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.lsu.edu/docs/available/etd-07092017-013450/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached herein a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to LSU or its agents the non-exclusive license to archive and make accessible, under the conditions specified below and in appropriate University policies, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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