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

Yan, Ru; Nanovskaya, Tatiana; Zharikova, Olga L.; Mattison, Donald R.; Hankins, Gary D.V.; Ahmed, Mahmoud S.

doi:10.1016/j.bcp.2008.01.013

Cited by 24 publications

(18 citation statements)

References 22 publications

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“…Identity of the major metabolite (M2 HH ) generated from human hepatocytes needs to be elucidated, although preliminary data based on retention time and LC/MS data analysis indicate M2 HH (m/z ϭ 445) to be similar to M2 HLM . Similar results have recently been reported by Yan et al (2008). The study, performed in HLMs, reported the lack of 17-OHPC cleavage to release caproate ester based on radio-HPLC experiment.…”

Section: Expressed P450ssupporting

confidence: 89%

Identification of Enzymes Involved in the Metabolism of 17α-Hydroxyprogesterone Caproate: An Effective Agent for Prevention of Preterm Birth

Sharma¹,

Ou²,

Strom³

et al. 2008

Drug Metab Dispos

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ABSTRACT:Preterm delivery, that is delivery before 37 completed weeks of gestation, is the major determinant of neonatal morbidity and mortality. Until recently, no effective therapies for prevention of preterm birth existed. In a recent multicentered trial, 17␣-hydroxyprogesterone caproate (17-OHPC) reduced the rate of preterm birth by 33% in a group of high-risk women. Limited pharmacologic data exist for this drug. The recommended dose is empiric; the metabolic pathways are not well defined especially in pregnant women; and the fetal exposure has not been quantified. To define the metabolic pathways of 17-OHPC we used human liver microsomes (HLMs), fresh human hepatocytes (FHHs), and expressed enzymes. HLMs in the presence of NADPH generated three metabolites, whereas two major metabolites were observed with FHHs. Metabolism of 17-OHPC was significantly inhibited by the CYP3A4 inhibitors ketoconazole and troleandomycin in HLM and FHH. Metabolism of 17-OHPC was significantly greater in FHH treated with the CYP3A inducers, rifampin and phenobarbital. Furthermore, studies with expressed enzymes showed that 17-OHPC is metabolized exclusively by CYP3A4 and CYP3A5. The caproic acid ester was intact in the major metabolites generated, indicating that 17-OHPC is not converted to the primary progesterone metabolite, 17␣-hydroxyprogesterone. In summary, this study shows that 17-OHPC is metabolized by CYP3A. Because CYP3A is involved in the oxidative metabolism of numerous commonly used drugs, 17-OHPC may be involved in clinically relevant metabolic drug interactions with coadministered CYP3A inhibitors or inducers.

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Section: Expressed P450ssupporting

confidence: 89%

Identification of Enzymes Involved in the Metabolism of 17α-Hydroxyprogesterone Caproate: An Effective Agent for Prevention of Preterm Birth

Sharma¹,

Ou²,

Strom³

et al. 2008

Drug Metab Dispos

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“…It is administered as a weekly intramuscular injection of 250 mg. Because almost all lipidsoluble xenobiotics enter the fetal system through placental transfer, there is a high probability that 17-OHPC will penetrate through the placental barrier and gain access to the fetal circulation. Studies performed by using the dual perfused placental lobule technique have shown that 17-OHPC is transferred to the fetal circulation (Yan et al, 2008). Furthermore, analysis of fetal cord blood has shown significant 17-OHPC levels (S. Sharma, R. Venkataramanan, and S. C. Strom, unpublished data), thus confirming the transplacental transport from the mother to the fetus.…”

Section: Introductionmentioning

confidence: 83%

“…This procedure enabled partial elucidation of the 17-OHPC metabolite structure in adult and fetal hepatocytes and its comparison with previously reported data in adult liver microsomes (Yan et al, 2008).…”

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confidence: 84%

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Metabolism of 17α-Hydroxyprogesterone Caproate, an Agent for Preventing Preterm Birth, by Fetal Hepatocytes

Sharma¹,

Ellis²,

Dorko³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Preterm delivery (i.e., delivery before 37 completed weeks of gestation) is a major determinant of neonatal morbidity and mortality. Until recently, no effective therapies for prevention of preterm birth existed. In a recent multicentered trial, 17␣-hydroxyprogesterone caproate (17-OHPC) was shown to reduce the rate of preterm birth by 33% in a group of high-risk women. Limited pharmacologic data exist for this drug.Previous studies have shown that CYP3A is involved in the metabolism of 17-OHPC. In this study, we evaluated the metabolism of 17-OHPC in adult and fetal human hepatocytes and in expressed cytochrome P450 enzymes. 17-OHPC was metabolized by expressed CYP3A7 and by fetal hepatocytes. The metabolite profile was qualitatively different between expressed CYP3A4 and CYP3A7. Expressed CYP3A4 demonstrated a significantly higher (>10 times) capacity to metabolize 17-OHPC than CYP3A7. Based on retention times, two unique metabolites were observed in the fetal and adult hepatocyte systems along with one common metabolite. The intrinsic clearance of 17-OHPC by fetal hepatocytes was observed to be one-half of that in adults. In summary, this study demonstrates that fetal hepatocytes and, in particular, the fetal form of CYP3A (i.e., CYP3A7) can metabolize 17-OHPC.Fetal drug exposure is an unavoidable risk associated with drug therapies in pregnant subjects. The role of metabolism, via phase I and II pathways, in regulating fetal exposure is relatively lesser known. Fetal metabolism and the presence of cytochromes P450 (P450s) in the fetal liver have been previously documented in the literature (Ackermann and Richter, 1977;Aranda et al., 1979;Rollins et al., 1979;Rane and Tomson, 1980;Wiebkin et al., 1985;Komori et al., 1990;Chiba et al., 1997;Ladona et al., 2000).17␣-Hydroxyprogesterone caproate (17-OHPC) is a synthetic steroidal analog that is administered during pregnancy (from the second trimester onward) to prevent preterm birth. It is administered as a weekly intramuscular injection of 250 mg. Because almost all lipidsoluble xenobiotics enter the fetal system through placental transfer, there is a high probability that 17-OHPC will penetrate through the placental barrier and gain access to the fetal circulation. Studies performed by using the dual perfused placental lobule technique have shown that 17-OHPC is transferred to the fetal circulation (Yan et al., 2008). Furthermore, analysis of fetal cord blood has shown significant 17-OHPC levels (S. Sharma, R. Venkataramanan, and S. C. Strom, unpublished data), thus confirming the transplacental transport from the mother to the fetus.Although teratology studies have indicated the safety of 17-OHPC in rodents and nonhuman primates, differences in drug metabolism between animals and humans are well known. For example, the drug-oxidizing capacities have been reported to develop relatively early in human fetuses, whereas this capability is only reported postnatally in experimental animals, especially nonprimates (Rane and Tomson, 1980). Thus, it is import...

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“…The induction of CYP1A1 by maternal cigarette smoking or drug abuse and the effect of steroids has been amply demonstrated (Paakki et al 2000a;Paakki et al 2000b). Recently, metabolism of the progesterone, 17 hydroxyprogeteron caproate, (17-HPC) was studied on placental microsomes revealing that the extent of 17-HPC metabolism was much lower than that by the liver (Yan et al 2008).…”

Section: Placental Microsomesmentioning

confidence: 99%

In Vitro Models Using the Human Placenta to Study Fetal Exposure to Drugs

Kovo

Golan

2008

Clinical medicine. Reproductive health

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Over the recent years there has been a gradual rise in the use of pharmaceuticals during pregnancy. Knowledge on placental drug transfer and metabolism has increased during the past decades as well. Investigation of the transplacental transfer of any therapeutically useful drug is essential to the understanding of its metabolic processes and is a prerequisite for its use during pregnancy. The purpose of this review is to give insight on the various techniques that have been developed to evaluate transplacental transfer of drugs and xenobiotics.

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

Cited by 24 publications

References 22 publications

Identification of Enzymes Involved in the Metabolism of 17α-Hydroxyprogesterone Caproate: An Effective Agent for Prevention of Preterm Birth

Identification of Enzymes Involved in the Metabolism of 17α-Hydroxyprogesterone Caproate: An Effective Agent for Prevention of Preterm Birth

Metabolism of 17α-Hydroxyprogesterone Caproate, an Agent for Preventing Preterm Birth, by Fetal Hepatocytes

In Vitro Models Using the Human Placenta to Study Fetal Exposure to Drugs

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