The effect of esterases on 17α-hydroxyprogesterone caproate

Yan, Ru; Fokina, Valentina M.; Hankins, Gary D.V.; Ahmed, Mahmoud S.; Nanovskaya, Tatiana

doi:10.1016/j.ajog.2007.07.038

Cited by 14 publications

(9 citation statements)

References 11 publications

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“…This data is in agreement with recent reports on the lack of 17HPC hydrolysis by S9 fractions obtained from term 2,8 and preterm placentas 2 .…”

Section: Resultssupporting

confidence: 94%

“…If a prodrug, then there are at least two possible pathways for its metabolism (Figure 1): First, hydrolysis of the ester bond in 17-HPC by plasma or tissue esterases and thus the formation of 17α-hydroxyprogesterone (17HP) and caproate; Second, the oxidation or conjugation of 17HPC by cytochrome P450 isozymes or other enzymes, respectively. Recent investigations in our laboratory revealed that 17HPC is not hydrolyzed in vitro by either human plasma or tissue-derived preparations obtained from the liver, term and preterm placenta 2 . However, the absence of 17HPC hydrolysis in vitro does not exclude that it could be hydrolyzed in vivo.…”

Section: Introductionmentioning

confidence: 94%

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Transplacental transfer and metabolism of 17-α-hydroxyprogesterone caproate

Hemauer

Yan

Patrikeeva

et al. 2008

American Journal of Obstetrics and Gynecology

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Objective Determine transplacental transfer and metabolism of 17α-hydroxyprogesterone caproate (17-HPC) and its distribution between the tissue, maternal, and fetal circuits of the dually perfused placental lobule. Study design 17-HPC (21ng/ml) and its dual labeled isotope, 17α-hydroxy-[3H]progesterone [14C] caproate were added to the maternal circuit. The concentrations of the drug and its metabolite in trophoblast tissue and both circuits were determined by High Performance Liquid Chromatography (HPLC) and liquid scintillation spectrometry. Results The data obtained revealed that 17-HPC is transferred from the maternal to fetal circuit. At the end of a 4 hour perfusion period, a metabolite of 17-HPC that retained both progesterone and caproate moiety was identified in the tissue, maternal and fetal circuits. Neither 17-HPC nor its metabolite, at the concentrations tested, had any adverse effect on the determined viability and functional parameters of placental tissue. Conclusions 17α-hydroxyprogesterone caproate is metabolized by term placental lobule during its perfusion and both parent compound and its metabolite transferred to the fetal circuit.

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“…This data is in agreement with recent reports on the lack of 17HPC hydrolysis by S9 fractions obtained from term 2,8 and preterm placentas 2 .…”

Section: Resultssupporting

confidence: 94%

Section: Introductionmentioning

confidence: 94%

Transplacental transfer and metabolism of 17-α-hydroxyprogesterone caproate

Hemauer

Yan

Patrikeeva

et al. 2008

American Journal of Obstetrics and Gynecology

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“…A recent investigation in our laboratory revealed that 17-HPC was not hydrolyzed in vitro by human plasma and homogenates of human livers and placental trophoblast tissue [11]. Moreover, the drug was not hydrolyzed during its transfer across the dually perfused placental lobule but an unknown metabolite of 17-HPC was formed and partially identified [12].…”

Section: Discussionmentioning

confidence: 97%

“…Recent investigations in this laboratory on the in vitro hydrolysis of 17-HPC, radiolabeled in the progesterone [ 3 H] and caproate [ 14 C] revealed that the drug is neither hydrolyzed by human plasma, nor homogenates of human liver, term and preterm placentas [11]. Subsequent investigations on human placental transfer, metabolism and distribution of the radiolabeled 17-α-hydroxy-[ 3 H] progesterone [ 14 C] caproate utilizing dual perfused placental lobule revealed that 17-HPC was transferred to the fetal circuit, metabolized and retained by the placental tissue.…”

Section: Introductionmentioning

confidence: 99%

Metabolism of 17α-hydroxyprogesterone caproate by hepatic and placental microsomes of human and baboons

Yan

Nanovskaya

Zharikova

et al. 2008

Biochemical Pharmacology

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Recent data from our laboratory revealed the formation of an unknown metabolite of 17 hydroxyprogestrone caproate (17-HPC), used for treatment of preterm deliveries, during its perfusion across the dually perfused human placental lobule. Previously, we demonstrated that the drug is not hydrolyzed, neither in vivo nor in vitro, to progesterone and caproate. Therefore, the hypothesis for this investigation is that 17-HPC is actively metabolized by human and baboon (Papio cynocephalus) hepatic and placental microsomes. Baboon hepatic and placental microsomes were investigated to validate the nonhuman primate as an animal model for drug use during pregnancy. Data presented here indicate that human and baboon hepatic microsomes formed several mono-, di-, and tri-hydroxylated derivatives of 17-HPC. However, microsomes of human and baboon placentas metabolized 17-HPC to its mono-hydroxylated derivatives only in quantities that were a fraction of those formed by their respective livers, except for two metabolites (M16' and M17') that are unique for placenta and contributed to 25% and 75% of the total metabolites formed by human and baboon, respectively. The amounts of metabolites formed, relative to each other, by human and baboon microsomes were different suggesting that the affinity of 17-HPC to CYP enzymes and their activity could be species-dependent.

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“…The synthetic derivative 17OH-PC is resistant to metabolism by traditional steroid-transforming enzymes, and is thus unlikely to replicate all of the actions of natural progesterone. 17OH-PC is not a prodrug, and is not cleaved to 17 alpha-hydroxyprogesterone,24 a metabolite of progesterone already endogenously produced by the placenta in large amounts 25. The only metabolism observed with 17OH-PC is oxidation by cytochrome P450 3A in hepatocytes to monohydroxy, dihydroxy, and trihydroxy derivatives, with unknown resulting activity 26.…”

Section: Efficacy Of Hydroxyprogesterone Caproatementioning

confidence: 99%

Critical appraisal of the efficacy, safety, and patient acceptability of hydroxyprogesterone caproate injection to reduce the risk of preterm birth

Vidaeff¹,

Belfort²

2013

PPA

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Prevention of preterm delivery is a major desiderate in contemporary obstetrics and a societal necessity. The means to achieve this goal remain elusive. Progesterone has been used in an attempt to prevent preterm delivery since the 1970s, but the evidence initially accumulated was fraught by mixed results and was based on mostly underpowered studies with variable eligibility criteria, including history of spontaneous abortion as an indication for treatment. More recent randomized controlled clinical trials restimulated the interest in progesterone supplementation, suggesting that progesterone may favorably influence the rate of preterm delivery. Preterm delivery is a complex disorder and consequently it is unlikely that one generalized prevention strategy will be effective in all patients. Further, an additional impediment in accepting progesterone as the “magic bullet” in the prevention of preterm delivery is that its mechanism of action is not fully understood and the optimal formulations, route of administration, and dose have yet to be established. We have concerned ourselves in this review with the most recent status of 17 alpha-hydroxyprogesterone caproate (17OH-PC) supplementation for prevention of preterm delivery. Our intention is to emphasize the efficacy, safety, and patient acceptability of this intervention, based on a comprehensive and unbiased review of the available literature. Currently there are insufficient data to suggest that 17OH-PC is superior or inferior to natural progesterone. Based on available evidence, we suggest a differential approach giving preferential consideration to either 17OH-PC or other progestins based on obstetric history and cervical surveillance. Progestin therapy for risk factors other than a history of preterm birth and/or a short cervix in the current pregnancy is not currently supported by the published evidence. The experience to date with 17OH-PC indicates that there are population subgroups that may be harmed by administration of 17OH-PC. Therefore, extending the use of 17OH-PC to unstudied populations or for indications that are not evidence-based is inadvisable outside of a research protocol.

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The effect of esterases on 17α-hydroxyprogesterone caproate

Cited by 14 publications

References 11 publications

Transplacental transfer and metabolism of 17-α-hydroxyprogesterone caproate

Transplacental transfer and metabolism of 17-α-hydroxyprogesterone caproate

Metabolism of 17α-hydroxyprogesterone caproate by hepatic and placental microsomes of human and baboons

Critical appraisal of the efficacy, safety, and patient acceptability of hydroxyprogesterone caproate injection to reduce the risk of preterm birth

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