Effect of hepatic CYP inhibitors on the metabolism of sildenafil and formation of its metabolite, N-desmethylsildenafil, in rats in vitro and in vivo

Bae, Soo Hyeon; Bae, Soo Kyung; Lee, Myung G.

doi:10.1211/jpp.61.12.0008

Cited by 11 publications

(6 citation statements)

References 29 publications

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“…These doses are very common for rats, and we first aimed to determine if it is protective in CLP-induced organ damage, as well as how the dose affects protection. Therefore, we used 10-and 20-mg/kg oral doses of sildenafil, as have previous authors [35][36][37]. An equal volume of saline was administered to the sham-operated control group and the CLP group.…”

Section: Sepsis Modelmentioning

confidence: 99%

Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: a biochemical and histopathological study

Çadırcı¹,

Halıcı²,

Odabaşoğlu

et al. 2011

Clinical and Experimental Immunology

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SummarySepsis is a systemic inflammatory response to infection and a major cause of morbidity and mortality. Sildenafil (SLD) is a selective and potent inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase PDE5. We aimed to investigate the protective effects of sildenafil on caecal ligation and puncture (CLP)-induced sepsis in rats. Four groups of rats were used, each composed of 10 rats: (i) 10 mg/kg SLD-treated CLP group; (ii) 20 mg/kg SLD-treated CLP group; (iii) CLP group; and (iv) sham-operated control group. A CLP polymicrobial sepsis model was applied to the rats. All groups were killed 16 h later, and lung, kidney and blood samples were analysed histopathologically and biochemically. Sildenafil increased glutathione (GSH) and decreased the activation of myeloperoxidase (MPO) and of lipid peroxidase (LPO) and levels of superoxide dismutase (SOD) in the septic rats. We observed a significant decrease in LPO and MPO and a decrease in SOD activity in the sildenafil-treated CLP rats compared with the sham group. In addition, 20 mg/kg sildenafil treatment in the sham-operated rats improved the biochemical status of lungs and kidneys. Histopathological analysis revealed significant differences in inflammation scores between the sepsis group and the other groups, except the CLP + sildenafil 10 mg/kg group. The CLP + sildenafil 20 mg/kg group had the lowest inflammation score. Sildenafil treatment decreased the serum tumour necrosis factor (TNF)-a level when compared to the CLP group. Our results indicate that sildenafil is a highly protective agent in preventing lung and kidney damage caused by CLPinduced sepsis via maintenance of the oxidant-anti-oxidant status and decrease in the level of TNF-a.

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Section: Sepsis Modelmentioning

confidence: 99%

Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: a biochemical and histopathological study

Çadırcı¹,

Halıcı²,

Odabaşoğlu

et al. 2011

Clinical and Experimental Immunology

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“…Various studies have reported the effects of common organic solvents on the in vitro P450-mediated metabolic activities in human liver microsomes (HLM), human hepatocytes, or cDNA-expressed human microsomes (Cotreau-Bibbo et al, 1996;Draper et al, 1997;Chauret et al, 1998;Hickman et al, 1998;Busby et al, 1999;Coller et al, 1999;Palamanda et al, 2000). RLM were quite commonly used during in vitro studies (Yao et al, 2008;Bae et al, 2009;Pelkonen et al, 2009;Deroussent et al, 2010); however, fewer systemic studies about the effects of organic solvents on the activities of rat P450 enzymes have been reported, and those tested in rats were limited to an old system in which the S9 and older marker substrates were used (Kawalek and Andrews, 1980). A previous study (Martignoni et al, 2006) indicated that the species-specific P450 enzymes of CYP1A, CYP2C, CYP2D, and CYP3A showed appreciable interspecies differences in terms of catalytic activity between rats and humans.…”

Section: Introductionmentioning

confidence: 99%

Effect of Regular Organic Solvents on Cytochrome P450-Mediated Metabolic Activities in Rat Liver Microsomes

Li¹,

Han²,

Meng³

et al. 2010

Drug Metabolism and Disposition

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ABSTRACT:The effects of regular organic solvents on the metabolic activities of various human cytochromes P450 (P450s) have been reported. However, very little is known about their influence on metabolic activities mediated by P450s in the rat liver microsomes (RLM). The purpose of this study was to investigate the effects of organic solvents such as methanol, acetonitrile, dimethyl sulfoxide (DMSO), acetone, and ethanol on CYP1A, CYP2C, CYP2D, CYP2E, and CYP3A-mediated metabolism using RLM. The results showed that the activities of most rat P450 enzymes appeared to be organic solvent-dependent, and the metabolism of the tested probes were remarkably reduced when the concentration of organic solvents was up to 5% v/v, whereas most organic solvents demonstrated no significant interference when the concentration was below 1%, with the exception of DMSO. In addition, organic solvents exhibited different inhibitory effects, for example, CYP2D and CYP2E showed a significant reduction of activities at lower concentrations of organic solvents. Hence, this phenomenon should be taken into consideration when designing in vitro metabolism studies of new chemical entities. Therefore, we recommend acetonitrile as the most suitable solvent for RLM incubations, and the content of organic solvent should be kept lower than 1% v/v. IntroductionCytochromes P450 (P450s) are the principal enzymes for the oxidation of drugs, environmental pollutants, and a large number of xenobiotics, which present in many mammalian organs such as lungs, kidneys, intestines, and livers. Organic solvents are routinely used to dissolve substrates or other chemicals in the microsomal incubations for drug metabolism, P450 inhibition, and induction studies. For example, ethoxyresorufin and pentoxyresorufin are both hydrophobic substrates as the biomarkers for CYP1A1 and CYP2B1, dimethyl sulfoxide (DMSO), or ethanol/bovine serum albumin (BSA) were added to increase the solubility in rat liver microsomes (RLM) incubation system (Rutten et al., 1992). Various studies have reported the effects of common organic solvents on the in vitro P450-mediated metabolic activities in human liver microsomes (HLM), human hepatocytes, or cDNA-expressed human microsomes (Cotreau-Bibbo et al., 1996;Draper et al., 1997;Chauret et al., 1998;Hickman et al., 1998;Busby et al., 1999;Coller et al., 1999;Palamanda et al., 2000). RLM were quite commonly used during in vitro studies (Yao et al., 2008;Bae et al., 2009;Pelkonen et al., 2009;Deroussent et al., 2010); however, fewer systemic studies about the effects of organic solvents on the activities of rat P450 enzymes have been reported, and those tested in rats were limited to an old system in which the S9 and older marker substrates were used (Kawalek and Andrews, 1980). A previous study (Martignoni et al., 2006) indicated that the species-specific P450 enzymes of CYP1A, CYP2C, CYP2D, and CYP3A showed appreciable interspecies differences in terms of catalytic activity between rats and humans. Hence, the sensitivity of the P450 en...

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“…In male SD rats, sildenafil is metabolized via hepatic CYP2C11 and 3A1/2, and N ‐desmethylsildenafil was formed via CYP2C11 . After i.v.…”

Section: Drugsmentioning

confidence: 97%

Pharmacokinetic changes of drugs in a rat model of liver cirrhosis induced by dimethylnitrosamine, alone and in combination with diabetes mellitus induced by streptozotocin

Lee

2014

Biopharm & Drug Disp

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Rats with liver cirrhosis induced by N-dimethylnitrosamine (LC) and rats with LC with diabetes mellitus induced by streptozotocin (LCD) have been developed as animal models for human liver cirrhosis and liver cirrhosis with diabetes mellitus, respectively. Changes in the pharmacokinetics of drugs (mainly non-renal clearance, CL NR ) in LC and LCD rats reported in the literature compared with respective control rats were reviewed. This review mainly explains the changes in the CL NR s of drugs (which are mainly metabolized via hepatic microsomal cytochrome P450s, CYPs) in LC and LCD rats, in terms of the changes in in vitro hepatic intrinsic clearance (CL int ; mainly due to the changes in CYPs in the disease state), free (unbound) fraction of a drug in the plasma (f p ) and hepatic blood flow rate (Q H ) depending on the hepatic excretion ratio of the drug. Generally, changes in the CL NR s of drugs in LC and LCD rats could be well explained by the above-mentioned three factors. The mechanism of urinary excretion of drugs (such as glomerular filtration or renal active secretion or reabsorption) in LC and LCD rats is also discussed. The pharmacokinetics of the drugs reported in the LC and LCD rats were scarce in humans. Thus, the present rat data should be extrapolated carefully to humans.

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Effect of hepatic CYP inhibitors on the metabolism of sildenafil and formation of its metabolite, N-desmethylsildenafil, in rats in vitro and in vivo

Abstract: Sildenafil is metabolised via hepatic CYP2C11 and 3A1/2, and N-desmethylsildenafil is mainly formed via hepatic CYP2C11 in rats. Thus, rats could be a good model for pharmacokinetic studies of sildenafil and N-desmethylsildenafil in humans.

Cited by 11 publications

References 29 publications

Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: a biochemical and histopathological study

Sildenafil treatment attenuates lung and kidney injury due to overproduction of oxidant activity in a rat model of sepsis: a biochemical and histopathological study

Effect of Regular Organic Solvents on Cytochrome P450-Mediated Metabolic Activities in Rat Liver Microsomes

Pharmacokinetic changes of drugs in a rat model of liver cirrhosis induced by dimethylnitrosamine, alone and in combination with diabetes mellitus induced by streptozotocin

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