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

Sharma, Shringi; Ou, Junhai; Strom, Stephen C.; Mattison, Donald R.; Caritis, Steve N.; Venkataramanan, Raman

doi:10.1124/dmd.108.021444

Cited by 29 publications

(29 citation statements)

References 12 publications

(9 reference statements)

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“…Furthermore, the expression of drug transporters in fetal and adult human hepatocytes was evaluated. Dual-labeled 17-OHPC used in our study was observed to retain both ( 14 C, 3 H) labels after metabolism to mono-, di-, and tri-hydroxy derivatives, the major metabolites generated on incubations with adult and fetal hepatocyte cultures (Caritis et al, 2011 ;Sharma et al, 2008). Thus, the findings in our study refer to the disposition of 17-OHPC and its metabolites; in using the current study design, any difference between the parent compound and its metabolites cannot be differentiated.…”

Section: Discussionmentioning

confidence: 79%

“…Our first aim was to measure the functional activity of hepatic transporters in primary cultures of fetal hepatocytes using sodium taurocholate as a substrate of sodiumdependent uptake transporter, SLC10A1 (NTCP), and the bile salt efflux transporter, ABCB11 (BSEP). Our second aim was to determine whether transport processes were involved in the disposition of 17a-hydroxyprogesterone caproate (17-OHPC), a new progesterone analog administered to pregnant women to prevent preterm delivery (Meis et al, 2003;Sharma et al, 2008). Progesterone metabolites (PMs) have been reported to play a role in the etiology of ICP.…”

Section: Introductionmentioning

confidence: 99%

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Hepatobiliary Disposition of 17-OHPC and Taurocholate in Fetal Human Hepatocytes: A Comparison with Adult Human Hepatocytes

et al. 2012

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Little information is available in the literature regarding the expression and activity of transporters in fetal human liver or cultured cells. A synthetic progesterone structural analog, 17a-hydroxyprogesterone caproate (17-OHPC), is used in the prevention of spontaneous abortion in women with a history of recurrent miscarriage (habitual abortion). 17-OHPC has been reported to traverse the placental barrier and gain access to fetal circulation. In this study, the role of transporters in the disposition of 17-OHPC in fetal and adult human hepatocytes was examined. Progesterone metabolites have been reported to induce transinhibition of bile acid transporter, ABCB11. Thus, we investigated the effect of 17-OHPC or its metabolites on [ 3 H]taurocholic acid transport in sandwich-cultured human fetal and adult hepatocytes. 17-OHPC was taken up rapidly into the cells and transported out partially by an active efflux process that was significantly inhibited by cold temperature, cyclosporine, verapamil, and rifampin. The active efflux mechanism was observed in both adult and fetal hepatocyte cultures. 17-OHPC produced a concentrationdependent inhibition of taurocholate efflux into canaliculi in sandwich-cultured adult and fetal human hepatocytes. However, given the high concentrations required to cause inhibition of these transport processes, no adverse effects would be anticipated from therapeutic levels of 17-OHPC. We also evaluated the expression of various hepatic transporters (ABCB1, ABCB4, SLCO1B1, SLCO1B3, SLCO2B1, ABCB11, SLC10A1, ABCC2, ABCC3, ABCC4, and ABCG2) in fetal and adult hepatocytes. With the exception of ABCB4, all transporters examined were expressed, albeit at lower mRNA levels in fetal hepatocytes compared with adults.

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Hepatobiliary Disposition of 17-OHPC and Taurocholate in Fetal Human Hepatocytes: A Comparison with Adult Human Hepatocytes

et al. 2012

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“…Thus, in spite of the lower 17-OHPC-metabolizing capability, the results suggest that CYP3A7 may play a major role in the fetal disposition of 17-OHPC. Although CYP3A5 has been observed to metabolize 17-OHPC (Sharma et al, 2008) much more efficiently than CYP3A4, it is less likely to play a significant role in fetal metabolism because the expression level is almost negligible (Hakkola et al, 2001). The relative metabolic capacities of adult and fetal hepatocytes were evaluated by estimating the half-life and intrinsic clearance of 17-OHPC (5 M) based on loss of parent drug experiments.…”

Section: Discussionmentioning

confidence: 99%

“…Based on the results of the full scan and previously published reports (Sharma et al, 2008;Yan et al, 2008) ϩ and its Na ϩ adduct). The results were used in the characterization of the kinetics of 17-OHPC and its metabolites.…”

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confidence: 99%

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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“…For these 73 (Table 3). [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73] The mean (± S.D.) and median CYP3A5/CYP3A4 ratios of the metabolic activities in these 47 reactions were 0.69 ± 1.23 and 0.28, respectively.…”

Section: Metabolic Activity Of Cyp3a4 and Cyp3a5mentioning

confidence: 99%

Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition

Niwa

Murayama

Yamazaki

2010

JOURNAL OF HEALTH SCIENCE

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A meta-analysis was performed on the reported literature regarding followings. First, values of the MichaelisMenten constants (K m ), maximal velocities (V max ), and intrinsic clearance (V max /K m ) and the metabolic activities mediated by human cytochrome P450 3A4 and/or 3A5; second, inhibition constants (K i ); and third, maximum inactivation rate constants (k inact ) to establish the contribution of P450 3A5 to drug metabolism. At least 120 of the 127 metabolic reactions investigated (> 94%) were catalyzed by P450 3A4 and by P450 3A5. In the 73 metabolic reactions for which data were available, the mean P450 3A5/P450 3A4 ratios of K m , V max , and V max /K m values were 1.93, 1.25, and 1.20, respectively, but the median ratios were 1.17, 0.64, and 0.56, respectively. In 14-18% of the metabolic reactions, the V max and V max /K m values for P450 3A5 were more than twice those for P450 3A4. The K i values for P450 3A5 were on average approximately 5 times those for P450 3A4. Five of 13 mechanism-based inhibitors of P450 3A4 (38%) did not exhibit similar mechanism-based inhibition of P450 3A5. These collective findings give insight into the contribution of polymorphic P450 3A5 to drug metabolism and adverse drug interactions.

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

Cited by 29 publications

References 12 publications

Hepatobiliary Disposition of 17-OHPC and Taurocholate in Fetal Human Hepatocytes: A Comparison with Adult Human Hepatocytes

Hepatobiliary Disposition of 17-OHPC and Taurocholate in Fetal Human Hepatocytes: A Comparison with Adult Human Hepatocytes

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

Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition

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