Metabolism of medroxyprogesterone acetate (MPA) via CYP enzymes in vitro and effect of MPA on bleeding time in female rats in dependence on CYP activity in vivo

Mimura, Nobuhito; Kobayashi, Kaoru; Nakamura, Yoshika; Shimada, Noriaki; Hosokawa, Masakiyo; Chiba, Kazuhiro

doi:10.1016/j.lfs.2003.05.004

Cited by 9 publications

(7 citation statements)

References 16 publications

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“…Alternatively, it is possible that subcortical brain regions may be more dependent on blood flow, making striatum more susceptible to postischemic vascular obstruction. Another potential effect of MPA may be related to enhanced cerebral microvascular thrombosis, as oral MPA has been shown to accentuate prothrombic side effects in female rats (Mimura et al, 2003) and to heighten procoagulant response to thrombin (Herkert et al, 2001). Finally, MPA may have differential effects in the striatum because of differences in progesterone-receptor distribution or increased vulnerability to excitotoxic injury subsequent to accumulation of MPA metabolites in the striatum compared with the cortex (Ciriza et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Effects of Combined Oral Conjugated Estrogens and Medroxyprogesterone Acetate on Brain Infarction Size after Experimental Stroke in Rat

Littleton-Kearney

Klaus

Hurn

2005

J Cereb Blood Flow Metab

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The reason that estrogen is strongly protective in various estrogen-deficient animal models while seemingly detrimental in postmenopausal women remains unclear. It hypothesized that prolonged oral medroxyprogesterone (MPA) plus oral conjugated equine estrogens (CEE) diminishes estrogen ability to reduce stroke damage in the rodent stroke model. To test the hypothesis, we fed ovariectomized rats CEE or MPA, or a combination of CEE and MPA (CEP), before inducing 120 min of reversible focal stroke, using the intraluminal filament model. After 22 h reperfusion, the brains were harvested and infarction volumes were quantified. Treatment with CEE alone or with CEP reduced cortical infarction volume. However, CEP failed to provide ischemic protection in subcortical regions. It was concluded that CEE alone, or with CEP, is neuroprotective in the cortex, but interactive effects between the hormones may counteract CEE beneficial effects in subcortical brain regions.

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Section: Discussionmentioning

confidence: 99%

Effects of Combined Oral Conjugated Estrogens and Medroxyprogesterone Acetate on Brain Infarction Size after Experimental Stroke in Rat

Littleton-Kearney

Klaus

Hurn

2005

J Cereb Blood Flow Metab

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“…Ketoconazole, a CYP3A inhibitor, inhibited the metabolite formation in both PLM and RLM incubation systems, which indicated the possible involvement of CYP3A in MPA metabolism. The involvement of CYP3A in MPA metabolism has also been confirmed in rats based on parent drug disappearance (Mimura et al, 2003). These results suggested that rat and minipig could be surrogate models for man in MPA metabolism study.…”

Section: Discussionmentioning

confidence: 61%

“…The preferred hydroxylation sites were 2-, 6-, and 21-positions (Sturm et al, 1991), with 6␤,21-dihydroxy-MPA as the main metabolite (Helmreich and Huseby, 1962;Fukushima et al, 1979). Although it has been extensively studied in vivo, MPA metabolism by modern methodology was relatively poorly documented (Dollery, 1998, M17-21;Lobo, 1999;Mimura et al, 2003). For example, the structures of the metabolites were mostly proposed by mass spectra and were not fully characterized.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate

Liu¹,

Zhao²,

Wang³

et al. 2008

Drug Metabolism and Disposition

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ABSTRACT:Medroxyprogesterone acetate (MPA) is one of the most frequently prescribed progestins for conception, hormone replacement therapy, and adjuvant endocrine therapy. MPA has a low oral bioavailability because of extensive metabolism; however, its metabolism was poorly documented. This study was intended to profile the phase I metabolites of MPA and the cytochrome P450 (P450) isoforms involved. After MPA was incubated with human liver microsomes and the NADPH-generating system, five main metabolites

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“…The known inhibitors selected for CYP1A2, CYP2C7, CYP2D1 and CYP3A2 were, respectively, α-naphthoflavone, sulfaphenazole, quinidine, and ketoconazole. The present study was designed to: (1) investigate the effect of PTS pretreatment on rat liver CYP content; (2) examine the kinetic parameters of PTS incubation metabolism toward CYP; (3) to identify the principal CYP isoforms that metabolize PTS; (4) assess the inhibitory mechanism of known inhibitors on PTS metabolism in vitro; (5) investigate the modulation effect of PTS on the activities of selected CYP isoforms.…”

Section: Introductionmentioning

confidence: 99%

Metabolism and effect of para-toluene-sulfonamide on rat liver microsomal cytochrome P450 from in vivo and in vitro studies

Zhou

Tang

Zhang

et al. 2006

Acta Pharmacologica Sinica

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Aim: To study the in vivo and in vitro metabolism and the effect of para-toluenesulfonamide (PTS) on cytochrome P450 enzymes (CYP450). Methods: Total CYP450 and microsome protein content were determined after iv pretreatment of rats with PTS. CYP-specific substrates were incubated with rat liver microsomes. Specific CYP isoform activities were determined by using HPLC. CYP chemical inhibitors added to the incubation mixture were used to investigate the principal CYP isoforms involved in PTS metabolism. The effect of PTS on CYP isoforms was investigated by incubating PTS with specific substrates. Results: The groups treated with 33 and 99 mg/kg per d PTS, respectively, had a total CYP content of 0.66±0.17 and 0.60±0.12 nmol/mg. The K m and V max were 92.2 µmol/L and 0.0137 nmol/min per mg protein. CYP2C7, CYP2D1 and CYP3A2 might contribute to PTS metabolism in the rat liver. The inhibitory effects of sulfaphenazole and ketoconazole on PTS metabolism were shown to have a mixed mechanism, whereas PTS metabolism was inhibited noncompetitively by quinidine. PTS had little effect on the activities of the selected CYP isoforms. Conclusion: Generally speaking, it is relatively safe for PTS to be co-administered with other drugs. However, care should be taken when administering PTS with CYP inhibitors and the substrates of CYP2C, CYP2D and CYP3A.

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Metabolism of medroxyprogesterone acetate (MPA) via CYP enzymes in vitro and effect of MPA on bleeding time in female rats in dependence on CYP activity in vivo

Cited by 9 publications

References 16 publications

Effects of Combined Oral Conjugated Estrogens and Medroxyprogesterone Acetate on Brain Infarction Size after Experimental Stroke in Rat

Effects of Combined Oral Conjugated Estrogens and Medroxyprogesterone Acetate on Brain Infarction Size after Experimental Stroke in Rat

Metabolic Profiling and Cytochrome P450 Reaction Phenotyping of Medroxyprogesterone Acetate

Metabolism and effect of para-toluene-sulfonamide on rat liver microsomal cytochrome P450 from in vivo and in vitro studies

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