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| Clinical data | |
|---|---|
| Trade names | Prodrox |
| Other names | OHPA; 17α-Hydroxyprogesterone acetate; 17α-Acetoxyprogesterone; Acetoxyprogesterone; 17α-Hydroxypregn-4-ene-3,20-dione 17α-acetate; 17α-Acetoxypregn-4-ene-3,20-dione |
| Routes of administration | By mouth |
| Drug class | Progestogen;Progestin;Progestogen ester |
| ATC code | |
| Identifiers | |
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| CAS Number |
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| PubChemCID | |
| ChemSpider | |
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| KEGG | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.005.564 |
| Chemical and physical data | |
| Formula | C23H32O4 |
| Molar mass | 372.505 g·mol−1 |
| 3D model (JSmol) | |
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Hydroxyprogesterone acetate (OHPA), sold under the brand nameProdox, is anorally activeprogestin related tohydroxyprogesterone caproate (OHPC) which has been used inclinical andveterinary medicine.[1][2][3][4][5][6][7][8] It has reportedly also been used inbirth control pills.[9]
OHPA is a progestin, or asyntheticprogestogen, and hence is anagonist of theprogesterone receptor, thebiological target of progestogens likeprogesterone.
OHPA was discovered in 1953 and was introduced for medical use in 1956.[10][11][12]
OHPA has been used in the treatment of a variety ofgynecological disorders, includingsecondary amenorrhea,functional uterine bleeding,infertility,habitual abortion,dysmenorrhea, andpremenstrual syndrome.[3][13][14]
OHPA (100 mg) was reportedly marketed in combination withmestranol (80 μg) as a sequentialcombined birth control pill under the brand name Hormolidin.[9] The preparation was available in the early 1970s.[9] The firm that manufactured it, known as Gador, was based inArgentina.[9]
OHPA is aprogestogen and acts as anagonist of theprogesterone receptor (PR), bothPRA andPRBisoforms (IC50 = 16.8 nM and 12.6 nM, respectively).[15] It has more than 50-fold higher affinity for the PR isoforms than17α-hydroxyprogesterone, a little less than half the affinity ofprogesterone, and slightly higher affinity than OHPC.[16] Additional studies have reported on the affinity of OHPA for the PR.[17][18][19][20][21]
OHPA is of relatively lowpotency as a progestogen, which may explain its relatively limited use.[22] It is 100-fold less potent thanmedroxyprogesterone acetate, 400-fold less potent thanchlormadinone acetate, and 1,200-fold less potent thancyproterone acetate inanimalassays.[22] In terms of producing full progestogenic changes on theendometrium in women, 75 to 100 mg/day oral OHPA is equivalent to 20 mg/day parenteral progesterone, and OHPA is at least twice as potent as oralethisterone in such regards.[3] It is also reportedly more potent than OHPC.[15][23] OHPA has been found to be effective as an oralprogestogen-only pill at a dosage of 30 mg/day.[24]
| Compound | hPR-A | hPR-B | rbPR | rbGR | rbER | |||
|---|---|---|---|---|---|---|---|---|
| Progesterone | 100 | 100 | 100 | <1 | <1 | |||
| 17α-Hydroxyprogesterone | 1 | 1 | 3 | 1 | <1 | |||
| Hydroxyprogesterone caproate | 26 | 30 | 28 | 4 | <1 | |||
| Hydroxyprogesterone acetate | 38 | 46 | 115 | 3 | ? | |||
| Notes: Values are percentages (%). Referenceligands (100%) wereprogesterone for thePRTooltip progesterone receptor,dexamethasone for theGRTooltip glucocorticoid receptor, andestradiol for theERTooltip estrogen receptor.Sources: See template. | ||||||||
OHPA has very low but nonetheless significantoralbioavailability and can be taken by mouth.[25] Thepharmacokinetics of OHPA have been reviewed.[2]
A singleintramuscular injection of 150 to 350 mg OHPA inmicrocrystallineaqueous suspension has been found to have aduration of action of 9 to 16 days in terms of clinicalbiological effect in theuterus in women.[26]
| Compound | Form | Dose for specific uses (mg)[c] | DOA[d] | |||
|---|---|---|---|---|---|---|
| TFD[e] | POICD[f] | CICD[g] | ||||
| Algestone acetophenide | Oil soln. | – | – | 75–150 | 14–32 d | |
| Gestonorone caproate | Oil soln. | 25–50 | – | – | 8–13 d | |
| Hydroxyprogest. acetate[h] | Aq. susp. | 350 | – | – | 9–16 d | |
| Hydroxyprogest. caproate | Oil soln. | 250–500[i] | – | 250–500 | 5–21 d | |
| Medroxyprog. acetate | Aq. susp. | 50–100 | 150 | 25 | 14–50+ d | |
| Megestrol acetate | Aq. susp. | – | – | 25 | >14 d | |
| Norethisterone enanthate | Oil soln. | 100–200 | 200 | 50 | 11–52 d | |
| Progesterone | Oil soln. | 200[i] | – | – | 2–6 d | |
| Aq. soln. | ? | – | – | 1–2 d | ||
| Aq. susp. | 50–200 | – | – | 7–14 d | ||
Notes and sources:
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OHPA, also known as 17α-hydroxyprogesterone acetate or as 17α-acetoxypregn-4-ene-3,20-dione, is asyntheticpregnanesteroid and aderivative ofprogesterone.[1][46] It is theacetateester of17α-hydroxyprogesterone, as well as aparent compound of a number of progestins includingchlormadinone acetate,cyproterone acetate,medroxyprogesterone acetate, andmegestrol acetate.[4][46]
Chemical syntheses of OHPA have been described.[2]
In 1949, it was discovered that17α-methylprogesterone had twice the progestogenic activity of progesterone when administeredparenterally,[47] and this finding led to renewed interest in 17α-substituted derivatives of progesterone as potential progestins.[12] Along with OHPC, OHPA wassynthesized by Karl Junkmann ofSchering AG in 1953 and was first reported by him in themedical literature in 1954.[10][11][48][49][12] OHPC shows very low oral activity[16] and was introduced for use viaintramuscular injection bySquibb in 1956 under the brand name Delalutin.[12] Although a substantial prolongation of action occurs when OHPC is formulated in oil,[16] the same was not observed to a significant extent with OHPA, and this is likely why OHPC was chosen by Schering for development over OHPA.[7]
Subsequently,Upjohn unexpectedly discovered that OHPA, unlike OHPC andprogesterone, is orally active and shows marked progestogenic activity with oral administration,[25] a finding that had been missed by the Schering researchers (who were primarily interested in the oil solubility of such esters).[7][12] OHPA was found to possess two to three times the oral activity of 17α-methylprogesterone.[50] Upjohn reported the oral activity of OHPA in the medical literature in 1957 and introduced the drug for medical use as Prodox in 25 mg and 50 mg oral tablet formulations later the same year.[3][12][13] OHPA was indicated for the treatment of a variety ofgynecological disorders in women.[3][13][14] However, it saw relatively little use, which was perhaps due its comparatively low potency relative to a variety of other progestins such asmedroxyprogesterone acetate andnorethisterone.[22][14] These progestins were introduced around the same time and hence may have been favored.[22][14]
In 1960, OHPA was introduced also as Prodox as an oral progestin for veterinary use for the indication ofestrus suppression in dogs.[8][51] However, probably due its high cost and the inconvenience of daily oral administration, the drug was not a market success.[8] It was superseded for this indication by medroxyprogesterone acetate (brand name Promone) in 1963, which could be administered by injection conveniently once every six months, although this preparation was discontinued in 1966 for various reasons and hence was not a market success either.[8]
Hydroxyprogesterone acetate is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name.[1]
OHPA is or was marketed under the brand name Prodox initially for clinical use and then for veterinary use.[1] Other brand names of OHPA include Gestageno, Gestageno Gador, Kyormon, Lutate-Inj, Prodix, and Prokan.[1] OHPA may also be or have been marketed in combination withestradiol enantate under the brand names Atrimon and Protegin inArgentina andNicaragua.[52]
OHPA is no longer marketed and hence is no longer available in any country.[53][54][52]
It is the purpose of this paper to introduce and describe a new steroid for oral administration, 17-a-hydroxyprogesterone acetate*, and to compare it with the most widely used oral substance with progestational properties, 20,21-anhydro-17-/3-hydroxyprogesterone. * Prodox, Upjohn Co., Kalamazoo, Michigan [...] It was found that 17-a-hydroxyprogesterone acetate has a progestational activity which is at least twice that of anhydrohydroxyprogesterone.
In 1954, Karl Junkmann of Schering AG reported that the acetylation of the 17-hydroxyl group of ethisterone provided a derivative suitable for formulating in oil for injection intramuscularly as a depot medication.79 There resulted widespread interest in preparing the acetates (and other esters) of various hydroxy-steroids. One such ester, Upjohn's 17-acetoxyprogesterone, provided to be a promising progestogen even though its hydroxy precursor was inactive. Unfortunately, it turned out that no significant prolongation of action was obtained by formulating it in oil. The Upjohn researchers, however, made the unexpected discovery that their acetoxy derivative was orally active, an observation that had been missed by the Schering group, who were primarily interested in the oil solubility of such esters.
[...] The first product was 17alpha-acetoxyprogesterone4 (Figure 1) marketed under the trade name of Prodox.® Prodox was introduced in 1960, was designed for oral use and was not a marketing success. The reasons are not clear as to lack of clear success, but one predominant reason was the high cost. For the average size dog, the cost of preventing estrus for a year was approximately $90. In addition, the inconvenience of daily oral administration may have prevented some market acceptance, especially at that cost. In 1963, Upjohn introduced injectable medroxyprogesterone acetate6 (Figure 1) under the trade name of Promone. Injections were to be made every six months, and this procedure was well accepted by both veterinarians and pet owners. However, Promone sales were discontinued in April, 1966 in the United States for basically two reasons. First was a prolonged and unpredictable return to estrus. This appeared to be due to very slow and variable absorption from the injection site. As a result of this variable absorption rate, one would expect a variable return to estrus. Even after [...]
Chemically pure progesterone was the only substance with progestational properties in general use which could be administered parenterally until Junkmann (1) developed in 1953, 17-alpha-hydroxyprogesterone acetate and 17-alpha-hydroxyprogesterone caproate.
In the group of new parenteral progestational agents, three substances developed by Karl Junkmann1,2 are the most outstanding and interesting: 17a-hydroxyprogesterone caproate and 17a-hydroxyprogesterone acetate, introduced in 1953, and the most potent of all new parenteral progestational agents, 17-ethynyl-19-nortestosterone enanthate, introduced in 1956.
Junkmann of Schering, AG., however, was able to show that long chain esters of 17a-hydroxyprogesterones such as the 17a-caproate produced powerful long-acting progestational effect. [...] Subsequently, a series of events led to the exploitation of 17a-hydroxyprogesterone derivatives as highly effective and orally active progestogens. Groups at Upjohn, Merck & Co., and Syntex independently found means of readily acetylating the 17-hydroxy group. Later, Upjohn announced it found that 17a-acetoxyprogesterone was orally active in humans and subsequently marketed this compound under the name of Prodox.
Prodox Tablets ( Upjohn) A new derivative of progesterone for oral administration. Indications: Secondary amenorrhea, functional uterine bleeding, in- fertility, habitual abortion, dysmen-orrhea and premenstrual tension. Supplied: Tablets containing 25 mg. or 50 mg. of hydroxyprogesterone a c e t a te, in bottles of 25 tablets.
[...] ethisterone, 25 mg. (Lutocylol; Pranone) 17-acetoxyprogesterone, 25 mg. (Prodox), 6-methyl-17-acetoxyprogesterone, 5 mg. (Provera), norethindrone, 5 mg. (Norlutin), norethinodrel, 5 mg. (Enovid). [...]
Hydroxyprogesterone caproate appears to be even less active than Prodox in some respects. It is about 5 times progesterone as an endometrial stimulator [...]
Whereas progesterone is relatively inactive when administered orally, ethisterone (anhydrohydroxyprogesterone) and hydroxyprogesterone acetate are highly active.
17α-Hydroxyprogesterone caproate is a depot progestogen which is entirely free of side actions. The dose required to induce secretory changes in primed endometrium is about 250 mg. per menstrual cycle.
The results showed that after injection the concentration of plasma MA increased rapidly. The meantime of peak plasma MA level was 3rd day, there was a linear relationship between log of plasma MA concentration and time (day) after administration in all subjects, elimination phase half-life t1/2β = 14.35 ± 9.1 days.
[The] minimal activity [of 17(a)-hydroxyprogesterone] is magnified to an unexpected degree by the esterification of this steroid with caproic acid to produce 17(a)-hydroxyprogesterone-17-n-caproate, first reported by Karl Junkmann in 1954.6,7
Junkmann (1954) reported that the acetate, butyrate, and caproate forms had both increased and prolonged activity, [...]
Subsequent acetylation with acetic anhydride and tosyl acid followed by Oppenauer oxidation afforded 17a-acetoxy- progesterone (95) in good yield (115). Tests showed this compound to possess 2-3 times the oral activity of 17-methylpregn-4-ene-3,20-dione (78) and to be many times more potent than progesterone (116,117).
According to Dr. Gordon G. Stocking, director of Upjohn's Veterinary Division, Prodox is a synthetic version of progesterone — one of the hormones that regulates the human female reproductive system. It is 100 per cent effective and has produced no ill-effects on 200 or more dogs on which it has been tested. As a result of its findings, says Dr. Stocking, Upjohn is making the product available through veterinarians.