Inhibitor Of Cytochrome P450 Isozymes Research Articles

Modulation of cytochrome P450 metabolism and transport across intestinal epithelial barrier by ginger biophenolics.

Natural and complementary therapies in conjunction with mainstream cancer care are steadily gaining popularity. Ginger extract (GE) confers significant health-promoting benefits owing to complex additive and/or synergistic interactions between its bioactive constituents. Recently, we showed that preservation of natural “milieu” confers superior anticancer activity on GE over its constituent phytochemicals, 6-gingerol (6G), 8-gingerol (8G), 10-gingerol (10G) and 6-shogaol (6S), through enterohepatic recirculation. Here we further evaluate and compare the effects of GE and its major bioactive constituents on cytochrome P450 (CYP) enzyme activity in human liver microsomes by monitoring metabolites of CYP-specific substrates using LC/MS/MS detection methods. Our data demonstrate that individual gingerols are potent inhibitors of CYP isozymes, whereas GE exhibits a much higher half-maximal inhibition value, indicating no possible herb-drug interactions. However, GE's inhibition of CYP1A2 and CYP2C8 reflects additive interactions among the constituents. In addition, studies performed to evaluate transporter-mediated intestinal efflux using Caco-2 cells revealed that GE and its phenolics are not substrates of P-glycoprotein (Pgp). Intriguingly, however, 10G and 6S were not detected in the receiver compartment, indicating possible biotransformation across the Caco-2 monolayer. These data strengthen the notion that an interplay of complex interactions among ginger phytochemicals when fed as whole extract dictates its bioactivity highlighting the importance of consuming whole foods over single agents. Our study substantiates the need for an in-depth analysis of hepatic biotransformation events and distribution profiles of GE and its active phenolics for the design of safe regimens.

Effects of CYP inducers and inhibitors on the pharmacokinetics of intravenous theophylline in rats: involvement of CYP1A1/2 in the formation of 1,3-DMU

The types of hepatic cytochrome P450 (CYP) isozymes responsible for the metabolism of theophylline and for the formation of 1,3-dimethyluric acid (1,3-DMU) in rats in-vivo does not seem to have been studied at the dose ranges of dose-independent metabolic disposition of theophylline in rats (up to 10 mg kg(-1)). Therefore, theophylline (5 mg kg(-1)) was administered i.v. to male Sprague-Dawley rats pretreated with various inducers and inhibitors of CYP isozymes. In rats pretreated with 3-methylcholanthrene (3-MC), orphenadrine or dexamethasone (main inducers of CYP1A1/2, CYP2B1/2 and CYP3A1/2, respectively, in rats), the time-averaged non-renal clearance (CLNR) of theophylline was significantly faster than in their respective controls (1260, 42.7 and 69.0% increases, respectively). However, in rats pretreated with troleandomycin (a major inhibitor of CYP3A1/2 in rats), CLNR was significantly slower than in the controls (50.7% decrease). The 24 h urinary excretion of 1,3-DMU was increased significantly only in rats pretreated with 3-MC. The ratio of area under the curve for 1,3-DMU and theophylline (AUC1,3-DMU/AUCtheophylline) was increased significantly in rats pretreated with 3-MC (160% increase) and decreased significantly in rats pretreated with troleandomycin (50.1% decrease); however, the ratio was not increased in rats pretreated with dexamethasone. These data suggest that theophylline is primarily metabolized via CYP1A1/2, CYP2B1/2, and CYP3A1/2, and that 1,3-DMU is primarily formed via CYP1A1/2, and possibly CYP3A1/2, in rats.

Effects of cytochrome P450 (CYP) inducers and inhibitors on ondansetron pharmacokinetics in rats: involvement of hepatic CYP2D subfamily and 3A1/2 in ondansetron metabolism

The types of hepatic microsomal cytochrome P450 (CYP) isozymes responsible for the in-vivo metabolism of ondansetron in rats have not been reported. In this study, ondansetron at a dose of 8 mg kg(-1) was administered intravenously to rats pretreated with various inducers of CYP isozymes, such as 3-methylcholanthrene, orphenadrine citrate, isoniazid and dexamethasone phosphate (the main inducers of CYP1A1/2, 2B1/2, 2E1 and 3A1/2 in rats, respectively), and inhibitors, such as SKF-525A (a non-specific inhibitor of CYP isozymes), sulfaphenazole, quinine hydrochloride and troleandomycin (the main inhibitors of CYP2C6, 2D subfamily and 3A1/2 in rats, respectively). In rats pretreated with quinine hydrochloride and troleandomycin, the time-averaged non-renal clearance of ondansetron was significantly slower (48.9 and 13.2% decrease, respectively) than that in control rats. In rats pretreated with dexamethasone phosphate, the time-averaged non-renal clearance was significantly faster (18.2% increase) than that in control rats. The results suggest that ondansetron is primarily metabolized via the CYP2D subfamily and 3A1/2 in rats.

Effects of cytochrome P450 inducers and inhibitors on the pharmacokinetics of intravenous furosemide in rats: involvement of CYP2C11, 2E1, 3A1 and 3A2 in furosemide metabolism

Abstract Objectives It has been reported that the non-renal clearance of furosemide was significantly faster in rats pretreated with phenobarbital but was not altered in rats pretreated with 3-methylcholanthrene. However, no studies on other cytochrome P450 (CYP) isozymes have yet been reported in rats. Method Furosemide 20 mg/kg was administered intravenously to rats pretreated with various CYP inducers –3-methylcholanthrene, orphenadrine citrate and isoniazid, inducers of CYP1A1/2, 2B1/2 and 2E1, respectively, in rats – and inhibitors – SKF-525A (a nonspecific inhibitor of CYP isozymes), sulfaphenazole, cimetidine, quinine hydrochloride and troleandomycin, inhibitors of CYP2C6, 2C11, 2D and 3A1/2, respectively, in rats. Key findings The non-renal clearance of furosemide was significantly faster (55.9% increase) in rats pretreated with isoniazid, but slower in those pretreated with cimetidine or troleandomycin (38.5% and 22.7% decreases, respectively), than controls. After incubation of furosemide with baculovirus-infected insect cells expressing CYP2C11, 2E1, 3A1 or 3A2, furosemide was metabolized via CYP2C11, 2E1, 3A1 and 3A2. Conclusions These findings could help explain possible pharmacokinetic changes of furosemide in various rat disease models (where CYP2C11, 2E1, 3A1 and/or CYP3A2 are altered) and drug–drug interactions between furosemide and other drugs (mainly metabolized via CYP2C11, 2E1, 3A1 and/or 3A2).

Effects of cytochrome P450 inducers and inhibitors on the pharmacokinetics of intravenous furosemide in rats: involvement of CYP2C11, 2E1, 3A1 and 3A2 in furosemide metabolism

It has been reported that the non-renal clearance of furosemide was significantly faster in rats pretreated with phenobarbital but was not altered in rats pretreated with 3-methylcholanthrene. However, no studies on other cytochrome P450 (CYP) isozymes have yet been reported in rats. Furosemide 20 mg/kg was administered intravenously to rats pretreated with various CYP inducers--3-methylcholanthrene, orphenadrine citrate and isoniazid, inducers of CYP1A1/2, 2B1/2 and 2E1, respectively, in rats--and inhibitors--SKF-525A (a non-specific inhibitor of CYP isozymes), sulfaphenazole, cimetidine, quinine hydrochloride and troleandomycin, inhibitors of CYP2C6, 2C11, 2D and 3A1/2, respectively, in rats. The non-renal clearance of furosemide was significantly faster (55.9% increase) in rats pretreated with isoniazid, but slower in those pretreated with cimetidine or troleandomycin (38.5% and 22.7% decreases, respectively), than controls. After incubation of furosemide with baculovirus-infected insect cells expressing CYP2C11, 2E1, 3A1 or 3A2, furosemide was metabolized via CYP2C11, 2E1, 3A1 and 3A2. These findings could help explain possible pharmacokinetic changes of furosemide in various rat disease models (where CYP2C11, 2E1, 3A1 and/or CYP3A2 are altered) and drug-drug interactions between furosemide and other drugs (mainly metabolized via CYP2C11, 2E1, 3A1 and/or 3A2).

Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: An update

Background: The second-generation antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and other compounds with different mechanisms of action. All second-generation antidepressants are metabolized in the liver by the cytochrome P450 (CYP) enzyme system. Concomitant intake of inhibitors or inducers of the CYP isozymes involved in the biotransformation of specific antidepressants may alter plasma concentrations of these agents, although this effect is unlikely to be associated with clinically relevant interactions. Rather, concern about drug interactions with second-generation antidepressants is based on their in vitro potential to inhibit ≥1 CYP isozyme. Objective: The goal of this article was to review the current literature on clinically relevant pharmacokinetic drug interactions with second-generation antidepressants. Methods: A search of MEDLINE and EMBASE was conducted for original research and review articles published in English between January 1985 and February 2008. Among the search terms were drug interactions, second-generation antidepressants, newer antidepressants, SSRIs, SNRIs, fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, venlafaxine, duloxetine, mirtazapine, reboxetine, bupropion, nefazodone, pharmacokinetics, drug metabolism, and cytochrome P450. Only articles published in peerreviewed journals were included, and meeting abstracts were excluded. The reference lists of relevant articles were hand-searched for additional publications. Results: Second-generation antidepressants differ in their potential for pharmacokinetic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, and nefazodone is a substantial inhibitor of CYP3A4. Therefore, clinically relevant interactions may be expected when these antidepressants are coadministered with substrates of the pertinent isozymes, particularly those with a narrow therapeutic index. Duloxetine and bupropion are moderate inhibitors of CYP2D6, and sertraline may cause significant inhibition of this isoform, but only at high doses. Citalopram, escitalopram, venlafaxine, mirtazapine, and reboxetine are weak or negligible inhibitors of CYP isozymes in vitro and are less likely than other second-generation antidepressants to interact with co-administered medications. Conclusions: Second-generation antidepressants are not equivalent in their potential for pharmacokinetic drug interactions. Although interactions may be predictable in specific circumstances, use of an antidepressant with a more favorable drug-interaction profile may be justified.

P.2.c.017 The impact of reboxetine and mirtazapine on driving ability in depressed inpatients

Background: The second-generation antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and other compounds with different mechanisms of action. All second-generation antidepressants are metabolized in the liver by the cytochrome P450 (CYP) enzyme system. Concomitant intake of inhibitors or inducers of the CYP isozymes involved in the biotransformation of specific antidepressants may alter plasma concentrations of these agents, although this effect is unlikely to be associated with clinically relevant interactions. Rather, concern about drug interactions with second-generation antidepressants is based on their in vitro potential to inhibit ≥1 CYP isozyme.Objective: The goal of this article was to review the current literature on clinically relevant pharmacokinetic drug interactions with second-generation antidepressants.Methods: A search of MEDLINE and EMBASE was conducted for original research and review articles published in English between January 1985 and February 2008. Among the search terms were drug interactions, second-generation antidepressants, newer antidepressants, SSRIs, SNRIs, fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, venlafaxine, duloxetine, mirtazapine, reboxetine, bupropion, nefazodone, pharmacokinetics, drug metabolism, and cytochrome P450. Only articles published in peerreviewed journals were included, and meeting abstracts were excluded. The reference lists of relevant articles were hand-searched for additional publications.Results: Second-generation antidepressants differ in their potential for pharmacokinetic drug interactions. Fluoxetine and paroxetine are potent inhibitors of CYP2D6, fluvoxamine markedly inhibits CYP1A2 and CYP2C19, and nefazodone is a substantial inhibitor of CYP3A4. Therefore, clinically relevant interactions may be expected when these antidepressants are coadministered with substrates of the pertinent isozymes, particularly those with a narrow therapeutic index. Duloxetine and bupropion are moderate inhibitors of CYP2D6, and sertraline may cause significant inhibition of this isoform, but only at high doses. Citalopram, escitalopram, venlafaxine, mirtazapine, and reboxetine are weak or negligible inhibitors of CYP isozymes in vitro and are less likely than other second-generation antidepressants to interact with co-administered medications.Conclusions: Second-generation antidepressants are not equivalent in their potential for pharmacokinetic drug interactions. Although interactions may be predictable in specific circumstances, use of an antidepressant with a more favorable drug-interaction profile may be justified.

Effects of enzyme inducers and inhibitors on the pharmacokinetics of metformin in rats: involvement of CYP2C11, 2D1 and 3A1/2 for the metabolism of metformin

The types of hepatic microsomal cytochrome P450 (CYP) isozymes responsible for the metabolism of metformin in humans and rats have not been published to date. Therefore, a series of experiments using various inducers and inhibitors of CYP isozymes was conducted to find out what types of CYP isozymes are involved in the metabolism of metformin in rats. Metformin at a dose of 100 mg kg(-1) was administered intravenously to rats. The rats were pretreated with CYP inducers such as 3-methylcholanthrene, orphenadrine, isoniazid, and dexamethasone (major inducers of CYP1A1/2, 2B1/2, 2E1, and 3A1/2, respectively, in rats), or CYP inhibitors such as SKF-525 (a non-specific inhibitor of CYP isozymes), and sulfaphenazole, quinine, and troleandomycin (major inhibitors of CYP2C11, 2D1, and 3A1/2, respectively, in rats). The time-averaged non-renal clearance (CLNR) of metformin was compared with that of controls. In rats pretreated with dexamethasone, the CLNR was significantly faster (57% increase) than for the controls. In rats pretreated with SKF-525-A, sulfaphenazole, quinine, and troleandomycin, the CLNR was significantly slower (24.3, 62.9, 77.6, and 78.7% decrease, respectively) than for the controls. However, the CLNR values did not significantly different in the rats pretreated with 3-methylencholanthrene, orphenadrine, and isoniazid compared with the controls. Our data suggest that metformin was metabolized mainly via CYP2C11, 2D1, and 3A1/2 in rats. This result could contribute to understanding of the possible changes in metformin pharmacokinetics in disease models where CYP2C11 and/or 3A1/2 are altered.

Inhibition of cytochrome P450 isozymes and ornithine decarboxylase activities by polysaccharides from soybeans fermented with Phellinus igniarius or Agrocybe cylindracea.

Polysaccharides (5, 10, 25, 50 and 100 microg ml(-1)) from soybeans and soybeans fermented with Phellinus igniarius or Agrocybe cylindracea inhibited cytochrome P450 1A1, cytochrome P450 1A2 and cytochrome P450 2B1 activities in rat liver microsomes. The polysaccharides (5, 10 and 25 microg ml(-1)) also suppressed 12-O-tetradecanoylphorbol-13-acetate-induced ornithine decarboxylase activity. The most potent inhibitors of cytochrome P450 isozymes and ornithine decarboxylase activities were the polysaccharides from soybeans fermented with Agrocybe cylindracea.

Primaquine metabolism by human liver microsomes: effect of other antimalarial drugs

A number of drugs have been studied for their effect on the metabolism of the antimalarial drug primaquine by human liver microsomes (N = 4) in vitro. The only metabolite generated was identified as carboxyprimaquine by co-chromatography with the authentic standard. Ketoconazole, a known inhibitor of cytochrome P450 isozymes, caused marked inhibition of carboxyprimaquine formation with ic 50 and K i values of 15 and 6.7 μM, respectively. This finding and the dependency of metabolite formation on NADPH indicates that cytochrome P450 isozyme(s) catalysed metabolite production. Of compounds actually or likely to be coadministered with primaquine to malaria patients, only mefloquine produced any inhibition ( K i = 52.5 μM). Quinine, artemether, artesunate, halofantrine and chloroquine did not significantly inhibit metabolite formation. It seems unlikely that the concurrent administration of mefloquine, or other antimalarials, with primaquine will lead to appreciably altered disposition.

Mefloquine metabolism by human liver microsomes: Effect of other antimalarial drugs

A number of drugs have been studied for their effect on the metabolism of the antimalarial drug mefloquine by human liver microsomes (N = 6) in vitro. The only metabolite generated was identified as carboxymefloquine by co-chromatography with the authentic standard. Ketoconazole caused marked inhibition of carboxymefloquine formation with ic 50 and K i values of 7.5 and 11.2 μM, respectively. The inhibition by ketoconazole, a known inhibitor of cytochrome P450 isozymes, and the dependency of metabolite formation on the presence of NADPH indicated that cytochrome P450 isozyme(s) catalysed metabolite production. Of compounds actually or likely to be coadministered with mefloquine to malaria patients only primaquine and quinine produced marked inhibition ( ic 50, 17.5 and 122 μM; K i , 8.6 and 28.5 μM, respectively). However, despite these in vitro data with primaquine, clinical studies have failed to show any significant effect of single dose primaquine on the pharmacokinetics of mefloquine. With quinine, because peak plasma concentrations are very close to the K i value, there is likely to be inhibition of mefloquine metabolism in patients receiving both drugs. Sulfadoxine, artemether, artesunate and tetracycline did not significantly inhibit carboxymefloquine formation.

Benoxaprofen induced toxicity in isolated rat hepatocytes

The toxicity of benoxaprofen, a non-steroidal anti-inflammatory compound was investigated using rat hepatic microsomal and isolated hepatocyte suspensions. In microsomes, benoxaprofen produced a Type I binding spectra and competitively inhibited ( k i 380 μM) the oxidative metabolism of aminopyrine. Marked toxicity was observed following incubation of benoxaprofen with isolated hepatocytes from either untreated, phenobarbitone (PB) or 3-methylcholanthrene (3-MC) pretreated male rats. In untreated hepatocytes increases in the intracellular lactate/pyruvate (L/P) ratio and alanine aminotransferase (ALT) release were related to the benoxaprofen concentration and duration of incubation. Alterations in L/P ratio preceded the release of cytosolic ALT and at 4 h a well defined dose-response relationship existed between the benoxaprofen concentration and the observed increases in the L/P ratio and ALT release. Pretreatment of animals with either PB or 3-MC did not affect the temporal nature nor the magnitude of the hepatocyte response to benoxaprofen. In addition, inhibitors of cytochrome P-450 isozymes (SKF-525A, metyrapone and α-napthoflavone) were ineffective with regard to modifying the observed toxicity. The results of this study suggest that hepatic cytochrome P-450 mediated metabolism may not be implicated in the toxicity of benoxaprofen in isolated hepatocytes. However, alterations in the cellular redox state and evidence of plasma membrane bleb formation suggest that benoxaprofen may uncouple oxidative phosphorylation and disturb intracellular calcium ion homeostasis.