Levonorgestrel butanoate

Levonorgestrel butanoate
Clinical data
Other names	LNG-B; HRP-002; Levonorgestrel 17β-butanoate; 17α-Ethynyl-18-methyl-19-nortestosterone 17β-butanoate; 17α-Ethynyl-18-methylestr-4-en-17β-ol-3-one 17β-butanoate
Routes of; administration	Intramuscular injection
Drug class	Progestogen; Progestogen ester
ATC code	None;
Identifiers
	IUPAC name [(8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-3-oxo-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] butanoate;
CAS Number	86679-33-6;
PubChem CID	3086228;
ChemSpider	2342903;
UNII	L929CBB126;
CompTox Dashboard (EPA)	DTXSID801166916 ;
ECHA InfoCard	100.081.125
Chemical and physical data
Formula	C25H34O3
Molar mass	382.544 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CCCC(=O)O[C@]1(CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=CC(=O)CC[C@H]34)CC)C#C;
	InChI InChI=1S/C25H34O3/c1-4-7-23(27)28-25(6-3)15-13-22-21-10-8-17-16-18(26)9-11-19(17)20(21)12-14-24(22,25)5-2/h3,16,19-22H,4-5,7-15H2,1-2H3/t19-,20+,21+,22-,24-,25-/m0/s1; Key:GPKLGCALNRZIDS-AYEDEZQKSA-N;

Levonorgestrel butanoate (LNG-B) (developmental code name HRP-002),^[1]^[2] or levonorgestrel 17β-butanoate, is a steroidal progestin of the 19-nortestosterone group which was developed by the World Health Organization (WHO) in collaboration with the Contraceptive Development Branch (CDB) of the National Institute of Child Health and Human Development as a long-acting injectable contraceptive.^[3]^[4]^[5] It is the C17β butanoate ester of levonorgestrel, and acts as a prodrug of levonorgestrel in the body.^[4] The drug is at or beyond the phase III stage of clinical development, but has not been marketed at this time.^[3] It was first described in the literature, by the WHO, in 1983, and has been under investigation for potential clinical use since then.^[4]^[6]

Quick Facts Clinical data, Other names ...

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LNG-B has been under investigation as a long-lasting injectable contraceptive for women.^[7] A single intramuscular injection of an aqueous suspension of 5 or 10 mg LNG-B has a duration of 3 months,^[3]^[7] whereas an injection of 50 mg has a duration of 6 months.^[1] The drug was also previously tested successfully as a combined injectable contraceptive with estradiol hexahydrobenzoate, but this formulation was never marketed.^[7] LNG-B has been tested successfully in combination with testosterone buciclate as a long-lasting injectable contraceptive for men as well.^[8]^[9]

LNG-B may have several advantages over depot medroxyprogesterone acetate, including the use of much lower comparative dosages, reduced progestogenic side effects like hypogonadism and amenorrhea, and a more rapid return in fertility following discontinuation.^[7]^[10] The drug has a well-established safety record owing to the use of levonorgestrel as an oral contraceptive since the 1960s.^[7]

More information Compound, Form ...

Parenteral potencies and durations of progestogens^[a]^[b]
Compound	Form	Dose for specific uses (mg)^[c]			DOA^[d]
Compound	Form	TFD^[e]	POICD^[f]	CICD^[g]	DOA^[d]
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: Sources: ^[11]^[12]^[13]^[14]^[15]^[16]^[17]^[18]^[19]^[20]^[21]^[22]^[23]^[24]^[25]^[26]^[27]^[3]^[7]^[1] All given by intramuscular or subcutaneous injection. Progesterone production during the luteal phase is ~25 (15–50) mg/day. The OIDTooltip ovulation-inhibiting dose of OHPC is 250 to 500 mg/month. Duration of action in days. Usually given for 14 days. Usually dosed every two to three months. Usually dosed once monthly. Never marketed or approved by this route. In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4).

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[1]
King TL, Brucker MC, Kriebs JM, Fahey JO (21 October 2013). Varney's Midwifery. Jones & Bartlett Publishers. pp. 495–. ISBN 978-1-284-02542-2.
[2]
Bhasin S (13 February 1996). Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. John Wiley & Sons. pp. 401–. ISBN 978-0-471-13320-9.
[3]
Runnebaum BC, Rabe T, Kiesel L (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 429–. ISBN 978-3-642-73790-9.
[4]
Crabbé P, Archer S, Benagiano G, Diczfalusy E, Djerassi C, Fried J, Higuchi T (1983). "Long-acting contraceptive agents: design of the WHO Chemical Synthesis Programme". Steroids. 41 (3): 243–53. doi:10.1016/0039-128X(83)90095-8. PMID 6658872. S2CID 12896179.
[5]
Koetsawang S (1991). "The injectable contraceptive: present and future trends". Ann. N. Y. Acad. Sci. 626 (1): 30–42. Bibcode:1991NYASA.626...30K. doi:10.1111/j.1749-6632.1991.tb37897.x. PMID 1829341. S2CID 27008012.
[6]
Benagiano, G., & Merialdi, M. (2011). Carl Djerassi and the World Health Organisation special programme of research in human reproduction. Journal für Reproduktionsmedizin und Endokrinologie-Journal of Reproductive Medicine and Endocrinology, 8(1), 10-13. http://www.kup.at/kup/pdf/10163.pdf
[7]
Artini PG, Genazzani AR, Petraglia F (11 December 2001). Advances in Gynecological Endocrinology. CRC Press. pp. 105–. ISBN 978-1-84214-071-0.
[8]
Coutifaris C, Mastroianni L (15 August 1997). New Horizons in Reproductive Medicine. CRC Press. pp. 101–. ISBN 978-1-85070-793-6.
[9]
Singh SK (4 September 2015). Mammalian Endocrinology and Male Reproductive Biology. CRC Press. pp. 270–. ISBN 978-1-4987-2736-5.
[10]
Senanayake P, Potts M (14 April 2008). Atlas of Contraception, Second Edition. CRC Press. pp. 49–. ISBN 978-0-203-34732-4.
[11]
Knörr K, Beller FK, Lauritzen C (17 April 2013). Lehrbuch der Gynäkologie. Springer-Verlag. pp. 214–. ISBN 978-3-662-00942-0.
[12]
Knörr K, Knörr-Gärtner H, Beller FK, Lauritzen C (8 March 2013). Geburtshilfe und Gynäkologie: Physiologie und Pathologie der Reproduktion. Springer-Verlag. pp. 583–. ISBN 978-3-642-95583-9.
[13]
Labhart A (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 554–. ISBN 978-3-642-96158-8.
[14]
Horský J, Presl J (1981). "Hormonal Treatment of Disorders of the Menstrual Cycle". In Horsky J, Presl K (eds.). Ovarian Function and its Disorders: Diagnosis and Therapy. Developments in Obstetrics and Gynecology. Springer Science & Business Media. pp. 309–332. doi:10.1007/978-94-009-8195-9_11. ISBN 978-94-009-8195-9.
[15]
Ufer J (1969). The Principles and Practice of Hormone Therapy in Gynaecology and Obstetrics. de Gruyter. p. 49. ISBN 9783110006148. 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.
[16]
Pschyrembel W (1968). Praktische Gynäkologie: für Studierende und Ärzte. Walter de Gruyter. pp. 598, 601. ISBN 978-3-11-150424-7.
[17]
Ferin J (September 1972). "Effects, Duration of Action and Metabolism in Man". In Tausk M (ed.). Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents. Vol. II. Pergamon Press. pp. 13–24. ISBN 978-0080168128. OCLC 278011135.
[18]
Henzl MR, Edwards JA (10 November 1999). "Pharmacology of Progestins: 17α-Hydroxyprogesterone Derivatives and Progestins of the First and Second Generation". In Sitruk-Ware R, Mishell DR (eds.). Progestins and Antiprogestins in Clinical Practice. Taylor & Francis. pp. 101–132. ISBN 978-0-8247-8291-7.
[19]
Brotherton J (1976). Sex Hormone Pharmacology. Academic Press. p. 114. ISBN 978-0-12-137250-7.
[20]
Sang GW (April 1994). "Pharmacodynamic effects of once-a-month combined injectable contraceptives". Contraception. 49 (4): 361–85. doi:10.1016/0010-7824(94)90033-7. PMID 8013220.
[21]
Toppozada MK (April 1994). "Existing once-a-month combined injectable contraceptives". Contraception. 49 (4): 293–301. doi:10.1016/0010-7824(94)90029-9. PMID 8013216.
[22]
Bagade O, Pawar V, Patel R, Patel B, Awasarkar V, Diwate S (2014). "Increasing use of long-acting reversible contraception: safe, reliable, and cost-effective birth control" (PDF). World J Pharm Pharm Sci. 3 (10): 364–392. ISSN 2278-4357. Archived from the original (PDF) on 2017-08-10. Retrieved 2016-08-24.
[23]
Goebelsmann U (1986). "Pharmacokinetics of Contraceptive Steroids in Humans". In Gregoire AT, Blye RP (eds.). Contraceptive Steroids: Pharmacology and Safety. Reproductive Biology. Springer Science & Business Media. pp. 67–111. doi:10.1007/978-1-4613-2241-2_4. ISBN 978-1-4613-2241-2.
[24]
Becker H, Düsterberg B, Klosterhalfen H (1980). "[Bioavailability of cyproterone acetate after oral and intramuscular application in men (author's transl)]" [Bioavailability of Cyproterone Acetate after Oral and Intramuscular Application in Men]. Urologia Internationalis. 35 (6): 381–5. doi:10.1159/000280353. PMID 6452729.
[25]
Moltz L, Haase F, Schwartz U, Hammerstein J (May 1983). "[Treatment of virilized women with intramuscular administration of cyproterone acetate]" [Efficacy of Intra muscularly Applied Cyproterone Acetate in Hyperandrogenism]. Geburtshilfe und Frauenheilkunde. 43 (5): 281–7. doi:10.1055/s-2008-1036893. PMID 6223851. S2CID 260160042.
[26]
Wright JC, Burgess DJ (29 January 2012). Long Acting Injections and Implants. Springer Science & Business Media. pp. 114–. ISBN 978-1-4614-0554-2.
[27]
Chu YH, Li Q, Zhao ZF (April 1986). "Pharmacokinetics of megestrol acetate in women receiving IM injection of estradiol-megestrol long-acting injectable contraceptive". The Chinese Journal of Clinical Pharmacology. Archived from the original on 2021-05-25. Retrieved 2020-11-25. 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.

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[28] Sources: ^[11]^[12]^[13]^[14]^[15]^[16]^[17]^[18]^[19]^[20]^[21]^[22]^[23]^[24]^[25]^[26]^[27]^[3]^[7]^[1]

[29] All given by intramuscular or subcutaneous injection.

[30] Progesterone production during the luteal phase is ~25 (15–50) mg/day. The OIDTooltip ovulation-inhibiting dose of OHPC is 250 to 500 mg/month.

[31] Duration of action in days.

[32] Usually given for 14 days.

[33] Usually dosed every two to three months.

[34] Usually dosed once monthly.

[mark-35] Never marketed or approved by this route.

[div-36] In divided doses (2 × 125 or 250 mg for OHPC, 10 × 20 mg for P4).

[KingBrucker2013-1] [1]
King TL, Brucker MC, Kriebs JM, Fahey JO (21 October 2013). Varney's Midwifery. Jones & Bartlett Publishers. pp. 495–. ISBN 978-1-284-02542-2.

[Bhasin1996-2] [2]
Bhasin S (13 February 1996). Pharmacology, Biology, and Clinical Applications of Androgens: Current Status and Future Prospects. John Wiley & Sons. pp. 401–. ISBN 978-0-471-13320-9.

[RunnebaumRabe2012-3] [3]
Runnebaum BC, Rabe T, Kiesel L (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 429–. ISBN 978-3-642-73790-9.

[pmid6658872-4] [4]
Crabbé P, Archer S, Benagiano G, Diczfalusy E, Djerassi C, Fried J, Higuchi T (1983). "Long-acting contraceptive agents: design of the WHO Chemical Synthesis Programme". Steroids. 41 (3): 243–53. doi:10.1016/0039-128X(83)90095-8. PMID 6658872. S2CID 12896179.

[pmid1829341-5] [5]
Koetsawang S (1991). "The injectable contraceptive: present and future trends". Ann. N. Y. Acad. Sci. 626 (1): 30–42. Bibcode:1991NYASA.626...30K. doi:10.1111/j.1749-6632.1991.tb37897.x. PMID 1829341. S2CID 27008012.

[BenagianoMerialdi2011-6] [6]
Benagiano, G., & Merialdi, M. (2011). Carl Djerassi and the World Health Organisation special programme of research in human reproduction. Journal für Reproduktionsmedizin und Endokrinologie-Journal of Reproductive Medicine and Endocrinology, 8(1), 10-13. http://www.kup.at/kup/pdf/10163.pdf

[ArtiniGenazzani2001-7] [7]
Artini PG, Genazzani AR, Petraglia F (11 December 2001). Advances in Gynecological Endocrinology. CRC Press. pp. 105–. ISBN 978-1-84214-071-0.

[CoutifarisMastroianni1997-8] [8]
Coutifaris C, Mastroianni L (15 August 1997). New Horizons in Reproductive Medicine. CRC Press. pp. 101–. ISBN 978-1-85070-793-6.

[Singh2015-9] [9]
Singh SK (4 September 2015). Mammalian Endocrinology and Male Reproductive Biology. CRC Press. pp. 270–. ISBN 978-1-4987-2736-5.

[SenanayakePotts2008-10] [10]
Senanayake P, Potts M (14 April 2008). Atlas of Contraception, Second Edition. CRC Press. pp. 49–. ISBN 978-0-203-34732-4.

[KnörrBeller2013-11] [11]
Knörr K, Beller FK, Lauritzen C (17 April 2013). Lehrbuch der Gynäkologie. Springer-Verlag. pp. 214–. ISBN 978-3-662-00942-0.

[KnörrKnörr-Gärtner2013-12] [12]
Knörr K, Knörr-Gärtner H, Beller FK, Lauritzen C (8 March 2013). Geburtshilfe und Gynäkologie: Physiologie und Pathologie der Reproduktion. Springer-Verlag. pp. 583–. ISBN 978-3-642-95583-9.

[Labhart2012-13] [13]
Labhart A (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 554–. ISBN 978-3-642-96158-8.

[HorskyPresl1981-14] [14]
Horský J, Presl J (1981). "Hormonal Treatment of Disorders of the Menstrual Cycle". In Horsky J, Presl K (eds.). Ovarian Function and its Disorders: Diagnosis and Therapy. Developments in Obstetrics and Gynecology. Springer Science & Business Media. pp. 309–332. doi:10.1007/978-94-009-8195-9_11. ISBN 978-94-009-8195-9.

[Ufer1969-15] [15]
Ufer J (1969). The Principles and Practice of Hormone Therapy in Gynaecology and Obstetrics. de Gruyter. p. 49. ISBN 9783110006148. 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.

[Pschyrembel1968-16] [16]
Pschyrembel W (1968). Praktische Gynäkologie: für Studierende und Ärzte. Walter de Gruyter. pp. 598, 601. ISBN 978-3-11-150424-7.

[Ferin1972-17] [17]
Ferin J (September 1972). "Effects, Duration of Action and Metabolism in Man". In Tausk M (ed.). Pharmacology of the Endocrine System and Related Drugs: Progesterone, Progestational Drugs and Antifertility Agents. Vol. II. Pergamon Press. pp. 13–24. ISBN 978-0080168128. OCLC 278011135.

[HenzlEdwards1999-18] [18]
Henzl MR, Edwards JA (10 November 1999). "Pharmacology of Progestins: 17α-Hydroxyprogesterone Derivatives and Progestins of the First and Second Generation". In Sitruk-Ware R, Mishell DR (eds.). Progestins and Antiprogestins in Clinical Practice. Taylor & Francis. pp. 101–132. ISBN 978-0-8247-8291-7.

[Brotherton1976-19] [19]
Brotherton J (1976). Sex Hormone Pharmacology. Academic Press. p. 114. ISBN 978-0-12-137250-7.

[pmid8013220-20] [20]
Sang GW (April 1994). "Pharmacodynamic effects of once-a-month combined injectable contraceptives". Contraception. 49 (4): 361–85. doi:10.1016/0010-7824(94)90033-7. PMID 8013220.

[pmid8013216-21] [21]
Toppozada MK (April 1994). "Existing once-a-month combined injectable contraceptives". Contraception. 49 (4): 293–301. doi:10.1016/0010-7824(94)90029-9. PMID 8013216.

[BagadePawar2014-22] [22]
Bagade O, Pawar V, Patel R, Patel B, Awasarkar V, Diwate S (2014). "Increasing use of long-acting reversible contraception: safe, reliable, and cost-effective birth control" (PDF). World J Pharm Pharm Sci. 3 (10): 364–392. ISSN 2278-4357. Archived from the original (PDF) on 2017-08-10. Retrieved 2016-08-24.

[Goebelsmann1986-23] [23]
Goebelsmann U (1986). "Pharmacokinetics of Contraceptive Steroids in Humans". In Gregoire AT, Blye RP (eds.). Contraceptive Steroids: Pharmacology and Safety. Reproductive Biology. Springer Science & Business Media. pp. 67–111. doi:10.1007/978-1-4613-2241-2_4. ISBN 978-1-4613-2241-2.

[BeckerDüsterberg1980-24] [24]
Becker H, Düsterberg B, Klosterhalfen H (1980). "[Bioavailability of cyproterone acetate after oral and intramuscular application in men (author's transl)]" [Bioavailability of Cyproterone Acetate after Oral and Intramuscular Application in Men]. Urologia Internationalis. 35 (6): 381–5. doi:10.1159/000280353. PMID 6452729.

[MoltzHaase2008-25] [25]
Moltz L, Haase F, Schwartz U, Hammerstein J (May 1983). "[Treatment of virilized women with intramuscular administration of cyproterone acetate]" [Efficacy of Intra muscularly Applied Cyproterone Acetate in Hyperandrogenism]. Geburtshilfe und Frauenheilkunde. 43 (5): 281–7. doi:10.1055/s-2008-1036893. PMID 6223851. S2CID 260160042.

[WrightBurgess2012-26] [26]
Wright JC, Burgess DJ (29 January 2012). Long Acting Injections and Implants. Springer Science & Business Media. pp. 114–. ISBN 978-1-4614-0554-2.

[ChuLi1986-27] [27]
Chu YH, Li Q, Zhao ZF (April 1986). "Pharmacokinetics of megestrol acetate in women receiving IM injection of estradiol-megestrol long-acting injectable contraceptive". The Chinese Journal of Clinical Pharmacology. Archived from the original on 2021-05-25. Retrieved 2020-11-25. 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.

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[g]

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[15]

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Levonorgestrel butanoate

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See also

References

Clinical data

Other names	LNG-B; HRP-002; Levonorgestrel 17β-butanoate; 17α-Ethynyl-18-methyl-19-nortestosterone 17β-butanoate; 17α-Ethynyl-18-methylestr-4-en-17β-ol-3-one 17β-butanoate
Routes of administration	Intramuscular injection
Drug class	Progestogen; Progestogen ester
ATC code	None
Identifiers
IUPAC name [(8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-3-oxo-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] butanoate
CAS Number	86679-33-6
PubChem CID	3086228
ChemSpider	2342903
UNII	L929CBB126
CompTox Dashboard (EPA)	DTXSID801166916
ECHA InfoCard	100.081.125
Chemical and physical data
Formula	C₂₅H₃₄O₃
Molar mass	382.544 g·mol⁻¹
3D model (JSmol)	Interactive image
SMILES CCCC(=O)O[C@]1(CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=CC(=O)CC[C@H]34)CC)C#C
InChI InChI=1S/C25H34O3/c1-4-7-23(27)28-25(6-3)15-13-22-21-10-8-17-16-18(26)9-11-19(17)20(21)12-14-24(22,25)5-2/h3,16,19-22H,4-5,7-15H2,1-2H3/t19-,20+,21+,22-,24-,25-/m0/s1 Key:GPKLGCALNRZIDS-AYEDEZQKSA-N