Abstract
Recent data from our laboratory revealed the formation of an unknown metabolite of 17 hydroxyprogesterone 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1848-1857 |
| Number of pages | 10 |
| Journal | Biochemical Pharmacology |
| Volume | 75 |
| Issue number | 9 |
| DOIs | |
| State | Published - May 1 2008 |
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Keywords
- 17α-Hydroxyprogesterone caproate
- Baboon liver
- Baboon placenta
- Human liver
- Human placenta
- Metabolism
- Microsomes
- Preterm delivery
ASJC Scopus subject areas
- Pharmacology
Cite this
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; Ahmed, Mahmoud.
In: Biochemical Pharmacology, Vol. 75, No. 9, 01.05.2008, p. 1848-1857.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Metabolism of 17α-hydroxyprogesterone caproate by hepatic and placental microsomes of human and baboons
AU - Yan, Ru
AU - Nanovskaya, Tatiana
AU - Zharikova, Olga L.
AU - Mattison, Donald R.
AU - Hankins, Gary
AU - Ahmed, Mahmoud
PY - 2008/5/1
Y1 - 2008/5/1
N2 - Recent data from our laboratory revealed the formation of an unknown metabolite of 17 hydroxyprogesterone 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.
AB - Recent data from our laboratory revealed the formation of an unknown metabolite of 17 hydroxyprogesterone 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.
KW - 17α-Hydroxyprogesterone caproate
KW - Baboon liver
KW - Baboon placenta
KW - Human liver
KW - Human placenta
KW - Metabolism
KW - Microsomes
KW - Preterm delivery
UR - http://www.scopus.com/inward/record.url?scp=41949095956&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=41949095956&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2008.01.013
DO - 10.1016/j.bcp.2008.01.013
M3 - Article
C2 - 18329004
AN - SCOPUS:41949095956
VL - 75
SP - 1848
EP - 1857
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
SN - 0006-2952
IS - 9
ER -