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PubMed1998

Strain differences in CYP3A-mediated C-8 hydroxylation (1,3,7-trimethyluric acid formation) of caffeine in Wistar and Dark Agouti rats. Rapid metabolism of caffeine in debrisoquine poor metabolizer model rats.

We observed significant strain differences [Dark Agouti (DA) > Wistar] in 1,3,7-trimethyluric acid formation (C-8 hydroxylation) during caffeine metabolism, though not in N-demethylations, in adult male DA and Wistar rats. In contrast, adult female and immature male rats of both DA and Wistar strains did not show significant differences in activity levels of C-8 hydroxylation. Kinetic studies using liver microsomes revealed that adult male DA rats have a larger Vmax for C-8 hydroxylation than do Wistar rats. Troleandomycin (TAO), known as a cytochrome P450 (CYP) 3A inhibitor, and an anti-rat CYP3A2 polyclonal antibody effectively reduced C-8 hydroxylation by rat liver microsomes in a concentration-dependent manner, suggesting that C-8 hydroxylation in rats is mediated largely by an isoform(s) of the CYP3A subfamily. Troleandomycin and the antibody did not inhibit the N-demethylations of caffeine by rat liver microsomes. Treatment of rats with CYP3A inducers caused a marked increase in C-8 hydroxylase activity. These results indicate that the rat CYP3A subfamily is capable of catalyzing C-8 hydroxylation of caffeine as is the case for human CYP3A4. The results of western blotting analysis using anti CYP3A antiserum showed that the staining intensity of the protein band in DA rat liver microsomes was higher than that in Wistar rat liver microsomes. We concluded that marked sex-dependent strain differences in C-8 hydroxylation of caffeine between Wistar and DA rats are due to the differences in the levels of expression of CYP3A in these strains of rats.

Aging↗
PubMed1998

Inhibition of triazolam clearance by macrolide antimicrobial agents: in vitro correlates and dynamic consequences.

BACKGROUND: Macrolide antimicrobial agents may impair hepatic clearance of drugs metabolized by cytochrome P4503A isoforms. Potential interactions of triazolam, a substrate metabolized almost entirely by cytochrome P4503A in humans, with 3 commonly prescribed macrolides were identified using an in vitro metabolic model. The actual interactions, and their pharmacodynamic consequences, were verified in a controlled clinical study. METHODS: In an in vitro model using human liver microsomes, 250 mumol/L triazolam was incubated with ascending concentrations (0 to 250 mumol/L of troleandomycin, azithromycin, erythromycin, and clarithromycin. In a randomized, double-blind, 5-trial clinical pharmacokinetic-pharmacodynamic study, 12 volunteers received 0.125 mg triazolam orally, together with placebo, azithromycin, erythromycin, or clarithromycin. In a fifth trial they received placebo plus placebo. RESULTS: Mean 50% inhibitory concentrations versus 4-hydroxytriazolam formation in vitro were as follows: 3.3 mumol/L troleandomycin, 27.3 mumol/L erythromycin, 25.2 mumol/L clarithromycin, and greater than 250 mumol/L azithromycin. Apparent oral clearance of triazolam when given with placebo or azithromycin was nearly identical (413 and 416 mL/min), as were peak plasma concentrations (1.25 and 1.32 ng/mL) and elimination half-life (2.7 and 2.6 hours). Apparent oral clearance was significantly reduced (P < .05) during erythromycin and clarithromycin trials (146 and 95 mL/min). Peak plasma concentration was correspondingly increased, and elimination half-life was prolonged. The effects of triazolam on dynamic measures were nearly identical when triazolam was given with placebo or azithromycin, but benzodiazepine agonist effects were enhanced during erythromycin and clarithromycin trials. CONCLUSION: The in vitro model identifies macrolides that may impair triazolam clearance. Anticipated interactions, and their pharmacodynamic consequences in volunteer subjects, were verified in vivo.

Administration, Oral↗
PubMed2004

Role of cytochrome P4503A in cysteine S-conjugates sulfoxidation and the nephrotoxicity of the sevoflurane degradation product fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (compound A) in rats.

The volatile anesthetic sevoflurane is degraded to fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether (FDVE) in anesthesia machines. FDVE is nephrotoxic in rats. FDVE undergoes glutathione conjugation, subsequent conversion to cysteine and mercapturic acid conjugates, and cysteine conjugate metabolism by renal beta-lyase, which is a bioactivation pathway mediating nephrotoxicity in rats. Recent in vitro studies revealed cytochrome P4503A-catalyzed formation of novel sulfoxide metabolites of FDVE cysteine-S and mercapturic acid conjugates in rat liver and kidney microsomes. FDVE-mercapturic acid sulfoxides were more toxic than other FDVE conjugates to renal proximal tubular cells in culture. Nevertheless, the occurrence and toxicological significance of FDVE sulfoxides formation in vivo remain unknown. This investigation determined, in rats in vivo, the existence, role of P4503A, and nephrotoxic consequence of FDVE conjugates sulfoxidation. Rats were pretreated with dexamethasone, phenobarbital, troleandomycin, or nothing (controls) before FDVE, and then, nephrotoxicity, FDVE-mercapturate sulfoxide urinary excretion, and FDVE-mercapturate sulfoxidation by liver microsomes were assessed. The formation of FDVE-mercapturic acid sulfoxide metabolites in vivo and their urinary excretion were unambiguously established by mass spectrometry. Dexamethasone and phenobarbital increased, and troleandomycin decreased (i) liver microsomal FDVE-mercapturic acid sulfoxidation in vitro, (ii) FDVE-mercapturic acid sulfoxide urinary excretion in vivo, and (iii) FDVE nephrotoxicity in vivo assessed by renal histology, blood urea nitrogen concentrations, and urine volume and protein excretion. Urine 3,3,3-trifluoro-2-(fluoromethoxy)propanoic acid, reflecting beta-lyase-dependent FDVE-cysteine S-conjugates metabolism, was minimally affected by the pretreatments. These results demonstrate that FDVE S-conjugates undergo P4503A-catalyzed sulfoxidation in rats in vivo, and this sulfoxidation pathway contributes to nephrotoxicity. FDVE S-conjugates sulfoxidation constitutes a newly discovered mechanism of FDVE bioactivation and toxicification in rats, in addition to beta-lyase-catalyzed metabolism of FDVE-cysteine S-conjugates.

Anesthetics, Inhalation↗
PubMed2006

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.

BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSIONS AND IMPLICATIONS: 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.

Alcohol Oxidoreductases↗
PubMed2001

Bioactivation to free radicals and cytotoxicity of 1,1-dichloro-1-fluoroethane (HCFC-141b).

1. The in vitro bioactivation by rat liver microsomes and the cytotoxicity in rat hepatocytes of 1,1-dichloro-1-fluoroethane (HCFC-141b), a replacement for some ozone depleting chlorofluorocarbons (CFC), have been investigated. 2. Anaerobic incubations of liver microsomes from pyridine-induced rats with HCFC-141b in the presence of the spin-trapping agent N-t-butyl-alpha-phenylnitrone (PBN) resulted in the formation of a typical ESR radical signal. 3. In the presence of HCFC-141b, a dose-dependent formation of conjugated dienes was observed that was partially inhibited by PBN, glutathione (GSH) and vitamin C. Moreover, HCFC-141b increased the release of lactate dehydrogenase (LDH) and the depletion of cellular glutathione in isolated rat hepatocytes under both normoxic and hypoxic conditions. 4. HCFC-141b-dependent cytotoxicity was completely prevented by PBN under both conditions and it was partially prevented under normoxic conditions by the broad-spectrum P450 inhibitor metyrapone, the P4502E1 specific inhibitor 4-methylpyrazole and the P4503A-specific inhibitor troleandomycin. Interestingly, HCFC-141b-dependent glutathione depletion was not prevented by PBN, metyrapone, 4-methylpyrazole or troleandomycin, whereas two glutathione depletors, 2,6-dimethyl-2,5-heptadien-4-one (phorone) and diethylmaleate, partially prevented LDH release. 5. The present results indicate that HCFC-141b is reductively metabolized in vitro to free radical intermediates by P450, in particular by the CYP2E1 and, to a lower extent, CYP3A isoforms, leading to peroxidative membrane damage and glutathione-independent cytotoxicity.

Animals↗
PubMed1999

Role of CYP3A in bromperidol metabolism in rat in vitro and in vivo.

1. The aim was to identify whether CYP3A metabolizes bromperidol (BP), an antipsychotic drug, to form 4-fluorobenzoyl-propionic acid (FBPA) in hepatic microsomes from 8-week-old male Sprague-Dawley rats and to investigate whether an inhibitor or an inducer of CYP3A affects BP pharmacokinetics in rat. 2. In an in vitro study, only troleandomycin showed marked inhibition of FBPA formation among several specific CYP isozyme inhibitors studied including troleandomycin, diethyldithiocarbamate, furafylline and quinine. Anti-rat CYP3A2 serum inhibited FBPA formation by 80%, whereas other anti-rat CYP sera (1A1, 1A2, 2B1, 2C11, 2E1) only slightly inhibited it. 3. In a pharmacokinetic study, BP half-life was prolonged to 137% of the average control value by 7-day treatment with erythromycin, a CYP3A inhibitor, and shortened to 58% of the control by 2-day treatment with dexamethasone, a CYP3A inducer. BP clearance was reduced to 68% of the control by erythromycin and was increased to 145% of control by dexamethasone. 4. These results suggested that BP biotransformation is catalysed mainly by CYP3A to form FBPA in rat and that the modification of this enzyme activity would affect the pharmacokinetics of BP.

Animals↗
PubMed1988

Application of theophylline metabolite assays to the exploration of liver microsome oxidative function in man.

The effects on theophylline oxidative metabolism of 3 inhibitors of liver microsome activity--cimetidine, troleandomycin and ketoconazole--were investigated in 6 healthy volunteers. The 3 compounds increased plasma theophylline half-life by 73.6 +/- 15.6% (P less than 0.01), 107.8 +/- 9.7% (P less than 0.001) and 21.7 +/- 6.8% (P less than 0.02), respectively, and reduced plasma theophylline clearance by 38.3 +/- 4.8% (P less than 0.001), 51.4 +/- 2.4% (P less than 0.001), and 8.9 +/- 7.8% (NS), respectively. Troleandomycin inhibited to the same extent the 2 theophylline metabolism pathways: N-demethylation resulting in the formation of 1-methyluric acid (1-MU) and 3-methylxanthine (3-MX), and 8-hydroxylation resulting in the formation of 1,3-dimethyluric acid (1,3-DMU). The production clearances of these metabolites were almost equally depressed by 60.2 +/- 3.9%, 60.2 +/- 2.1%, and 51.7 +/- 4.5%, respectively. Cimetidine predominantly inhibited the N-demethylation pathway; the production clearances of 1-MU and 3-MX were depressed by 58.5 +/- 4.0% and 57.5 +/- 4.1% (P less than 0.001), respectively, whereas the production clearance of 1,3-DMU was depressed by 38.3 +/- 6.1% (P less than 0.001). Ketoconazole had no significant effect on the produciton clearances of theophylline metabolites. Measurement of theophylline metabolite formation clearances might be a useful test to explore liver microsome oxidative function.

Adult↗
PubMed1997

Contribution of cytochrome P450 3A pathway to bromocriptine metabolism and effects of ferrous iron and hypoxia-re-oxygenation on its elimination in the perfused rat liver.

The contribution of the cytochrome P450 3A pathway to bromocriptine metabolism, and the effects of ferrous iron and hypoxia-re-oxygenation on its elimination, were evaluated with the perfused rat liver. Outflow profiles of bromocriptine after bolus administration were estimated by moment analysis and dispersion model analysis. Kinetic parameters were not significantly changed by troleandomycin, a P450 3A inhibitor. The inhibition of bromocriptine metabolism by troleandomycin was 5.7 +/- 2.4%. These findings indicate that cytochrome P450 3A does not play an important role in bromocriptine elimination with the perfused rat liver. Elimination rate constant (ka) values were significantly increased by ferrous iron perfusion or hypoxia-re-oxygenation. Free-radical generation can, therefore, affect bromocriptine elimination. Our observations suggest that bromocriptine might be eliminated by scavenging of free radicals in the liver.

Amitrole↗
PubMed2006

Evaluation of time-dependent cytochrome P450 inhibition using cultured human hepatocytes.

Primary human hepatocytes in culture are commonly used to evaluate cytochrome P450 (P450) induction via an enzyme activity endpoint. However, other processes can confound data interpretation. To this end, the impact of time-dependent P450 inhibition in this system was evaluated. Using a substrate-cassette approach, P450 activities were determined after incubation with the prototypic inhibitors tienilic acid (CYP2C9), erythromycin, troleandomycin, and fluoxetine (CYP3A4). Kinetic analysis of enzyme inactivation in hepatocytes was used to describe the effect of these time-dependent inhibitors and derive the inhibition parameters kinact and KI) which generally were in good agreement with the values derived using recombinant P450s and human liver microsomes (HLMs). Tienilic acid selectively inhibited CYP2C9-dependent diclofenac 4'-hydroxylation activity, and erythromycin, troleandomycin, and fluoxetine inhibited CYP3A4-dependent midazolam 1'-hydroxylation in a time- and concentration-dependent manner. Fluoxetine also inhibited CYP2C19-dependent S-mephenytoin 4'-hydroxylation in a time- and concentration-dependent manner in hepatocytes, HLMs, and recombinant CYP2C19 (KI 0.4 microM and kinact 0.5 min(-1)). As expected, the effect of fluoxetine on CYP2D6 in hepatocytes was consistent with potent yet reversible inhibition. A very weak time-dependent CYP2C9 inhibitor (AZ1, a proprietary AstraZeneca compound; KI 30 microM and kinact 0.02 min(-1)) effectively abolished CYP2C9 activity over 24 h at low (micromolar) concentrations in primary cultured human hepatocytes. This work demonstrates that caution is warranted in the interpretation of enzyme induction studies with metabolically stable, weak time-dependent inhibitors, which may have dramatic inhibitory effects on P450 activity in this system. Therefore, in addition to enzyme activity, mRNA and/or protein levels should be measured to fully evaluate the P450 induction potential of a drug candidate.

Aged↗
PubMed2004

Different in vitro metabolism of paclitaxel and docetaxel in humans, rats, pigs, and minipigs.

We investigated cytochrome P450 (P450)-catalyzed metabolism of the important cancer drugs paclitaxel and docetaxel in rat, pig, minipig, and human liver microsomes and cDNA-expressed P450 enzymes. In rat microsomes, paclitaxel was metabolized mainly to C3'-hydroxypaclitaxel (C3'-OHP) and to a lesser extent to C2-hydroxypaclitaxel (C2-OHP), di-hydroxypaclitaxel (di-OHP), and another unknown monohydroxylated paclitaxel. In pig and minipig microsomes, this unknown hydroxypaclitaxel was the main metabolite, whereas C3'-OHP was a minor product. In minipigs, C2-OHP was the next minor product. In human liver microsomes, 6 alpha-hydroxypaclitaxel (6 alpha-OHP) was the main metabolite, followed by C3'-OHP and C2-OHP. Among different cDNA-expressed human P450 enzymes (CYP1A2, 1B1, 2A6, 2C9, 2E1, and 3A4), only CYP3A4 enzyme formed C3'-OHP and C2-OHP. Docetaxel was metabolized in pig, minipig, rat, and human liver microsomes mainly to hydroxydocetaxel (OHDTX), whereas CYP3A-induced rat microsomes produced primarily diastereomeric hydroxyoxazolidinones. Human liver microsomes from 10 different individuals formed OHDTX at different rates correlated with CYP3A4 content. Troleandomycin as a selective inhibitor of CYP3A inhibited the formation of C3'-OHP, C2-OHP, and di-OHP, as well as the unknown OHP produced in rat, minipig, and pig microsomes. In human liver microsomes, troleandomycin inhibited C3'-OHP and C2-OHP formation, and a suitable inhibitor of human CYP2C8, fisetin, strongly inhibited the formation of 6 alpha-OHP, known to be catalyzed by human CYP2C8. In conclusion, the metabolism of docetaxel is the same in all four species, but metabolism of paclitaxel is different, and 6 alpha-OHP remains a uniquely human metabolite. Pigs and minipigs compared with each other formed the same metabolites of paclitaxel.

Adolescent↗
PubMed1996

Effects of erythromycin and roxithromycin on oxidation of testosterone and nifedipine catalyzed by CYP3A4 in human liver microsomes.

Roxithromycin and erythromycin were incubated with rat and human liver microsomal or reconstituted cytochrome P450 (P450 or CYP) monooxygenase systems in the presence of an NADPH-generating system, and the effects of these chemicals on testosterone 6 beta-hydroxylation and nifedipine oxidation activities were compared with those of typical CYP3A4 inhibitors including ketoconazole, troleandomycin, and gestodene. Roxithromycin and erythromycin were found to be relatively weak inhibitors of testosterone 6 beta-hydroxylation and nifedipine oxidation activities by rat and human liver microsomes or by reconstituted systems containing CYP3A4/5. Formation of an inhibitory P450-metabolite complex was determined spectrally by incubating troleandomycin with human liver microsomes; the extents of the complex formation were lesser in liver microsomes of humans than those of rats treated with dexamethasone. Erythromycin and roxithromycin were also activated slightly by rat liver microsomes to form P450.Fe(II)-metabolite complex, although these chemicals caused very little or undetectable levels, respectively, of spectral changes by human liver microsomes even when a human sample which contained relatively high levels of CYP3A4 was used. These results suggested that roxithromycin and erythromycin were relatively less potent to inhibit CYP3A4-catalytic activities in human liver microsomes, because of their low capabilities to form P450.Fe(II)-metabolite complex.

Animals↗
PubMed2005

Paradoxical role of cytochrome P450 3A in the bioactivation and clinical effects of levo-alpha-acetylmethadol: importance of clinical investigations to validate in vitro drug metabolism studies.

OBJECTIVE: Levo-alpha-acetylmethadol (LAAM, levacetylmethadol) is a long-acting opioid agonist used for the prevention of opioid withdrawal. LAAM undergoes sequential N-demethylation to norLAAM and dinorLAAM, which are more potent and longer-acting than LAAM. Hepatic and intestinal microsomal N-demethylation in vitro is catalysed mainly by cytochrome P450 (CYP) 3A4; however, the role of CYP3A in LAAM disposition in humans in vivo is unknown. This investigation tested the hypothesis that CYP3A induction (or inhibition) would increase (or decrease) LAAM metabolism and bioactivation and, thus, clinical effects. It also related changes in LAAM disposition during enzyme inhibition or induction to any changes in pharmacological effect. METHODS: Healthy volunteers (n = 13) completed the three-way, randomised, balanced crossover study. Subjects received oral LAAM (0.25 mg/kg) after CYP3A induction (rifampicin [rifampin]), inhibition (troleandomycin) or nothing (controls). Plasma and urine LAAM, norLAAM and dinorLAAM were determined by electrospray high-performance liquid chromatography/mass spectrometry (HPLC/MS). Dark-adapted pupil diameter change from baseline (miosis) was the LAAM effect measure. Results were analysed by noncompartmental methods and by a combined pharmacokinetic/pharmacodynamic model. RESULTS: Compared with controls, CYP3A induction (or inhibition) decreased (or increased) plasma LAAM concentrations and mean area under the plasma concentration-time curve from time zero to infinity (AUC(infinity) 199 +/- 91 [control] versus 11.3 +/- 4.0 [rifampicin] and 731 +/- 229 ng . h/mL [troleandomycin]; p < 0.05), and increased (or decreased) median formation clearances of norLAAM (1740 versus 14 100 and 302 mL/h/kg; p < 0.05) and dinorLAAM (636 versus 7840 and 173 mL/h/kg; p < 0.05). Surprisingly, however, CYP3A induction (or inhibition) decreased (or increased) mean plasma metabolite AUC from 0 to 96 hours (AUC(96)) [norLAAM + dinorLAAM] (859 +/- 241 versus 107 +/- 48 and 1185 +/- 179 ng . h/mL; p < 0.05) and clinical effects (mean miosis AUC(96) 128 +/- 40 versus 22.5 +/- 14.9 and 178 +/- 81 mm . h; p < 0.05). Clinical effects were best correlated with plasma norLAAM concentrations. CONCLUSION: CYP3A mediates human LAAM N-demethylation and bioactivation to norLAAM and dinorLAAM in vivo. Paradoxically, however, CYP3A induction decreased and inhibition increased LAAM active metabolite concentrations and clinical effects. This suggests a CYP3A-mediated metabolic pathway leading to inactive metabolites, which predominates over CYP3A-dependent bioactivation. These results highlight the need for clinical investigations to validate in vitro drug metabolism studies.

Administration, Oral↗
PubMed1982

Cytochrome P-450 metabolic-intermediate complex formation and induction by macrolide antibiotics; a new class of agents.

1. By several criteria, macrolide antibiotics constitute a new class of nitrogenous cytochrome P-450 metabolic-intermediate complex-forming compounds. 2. Macrolide antibiotic metabolic-intermediate complexes are only formed in livers induced with phenobarbital or with the macrolide antibiotics themselves. The extent of metabolic-intermediate complex formation in microsomes from phenobarbital-induced rats is lower than that seen for members of the amphetamine and SKF 525-A classes of compounds. 3. Cytochrome P-450 induced by macrolide antibiotics, of which troleandomycin is the most potent, is extensively sequestered as a metabolic intermediate complex in vivo. 4. Cytochrome P-450 induced by troleandomycin differs, using several criteria, from those induced by phenobarbital, beta-naphthoflavone or SKF 525-A, and those present in uninduced rats.

Animals↗
PubMed1992

Identification of a constitutive form of cytochrome P-450 with high activity towards macrolide antibiotics in Syrian golden hamster liver.

The presence of cytochromes P450 belonging to the P450IIIA family was investigated in the liver of untreated Syrian golden hamsters and compared to those of untreated, phenobarbital- and dexamethasone-treated rats. The microsomal preparations from untreated Syrian golden hamster livers exhibited higher activities of N-demethylation towards the macrolide antibiotics, erythromycin and troleandomycin, than those from untreated and phenobarbital-treated rats. Western blots analysis revealed larger amounts of proteins immunorelated to the rat cytochrome P450IIIA1 isozyme in Syrian golden hamster liver than in untreated and phenobarbital-treated rats. The N-demethylation of erythromycin and troleandomycin were strongly inhibited after preincubation of the microsomes from Syrian golden hamsters with anti-P450IIIA1. We conclude that a cytochrome P450 belonging to the P450IIIA family is expressed constitutively in the liver from Syrian golden hamsters, whereas it is not in rat liver.

Animals↗
PubMed1982

[Drug interactions with macrolids compared action of two macrolids on liver microsomal activity ].

Pharmacokinetic parameters for elimination of antipyrine, regarded as a marker of the oxidative activity of liver microsomes, were studied in six health volunteers after oral administration of 1 g of the drug. Elimination half life and metabolic clearance were determined prior to (controls) and on day 2 of a treatment with troleandomycin (1500 mg/day), on days 7 and 14 of a treatment with midecamycin (1200 mg/day) and on days 7 and 14 of a treatment with phenobarbital (100 mg/day) as reference. A marked difference was evident between troleandomycin (whose inhibitor effects on the liver metabolism of certain drugs (ergot derivatives, theophylline, etc) are known, and midecamycin. This one had no inhibitor action and this finding is consistent with previous results bearing on the pharmacokinetics of theophylline during antibiotic therapy: only on the 14th day was a slight inductor effect seen, but it remained much lower than that of phenobarbital whose effects were significant on both the 7th and the 14th days.

Adult↗
PubMedDate not supplied

Evidence that the biotransformation of dapsone and monoacetyldapsone to their respective hydroxylamine metabolites in rat liver microsomes is mediated by cytochrome P450 2C6/2C11 and 3A1.

The formation of dapsone hydroxylamine (DDS-NOH) and monoacetyldapsone hydroxylamine (MADDS-NOH) was found to be greater in male vs. female rat liver microsomes, suggesting a role for either CYP2C11 or CYP3A2. Preincubation with cimetidine (selective for inhibition of CYP2C11), but not troleandomycin (selective for inhibition of CYP3A1/2), inhibited metabolite formation. Furthermore, incubation with monoclonal antibodies (Mabs) to CYP2C6/2C11 reduced metabolite formation to below the level of detection. Together, these data indicate that N-hydroxylation of DDS and MADDS in rat liver microsomes from untreated male rats is catalyzed by CYP2C6/2C11. Interestingly, dexamethasone pretreatment increased the hydroxylation of both metabolites. Preincubation with cimetidine or Mabs to CYP2C6/2C11 (at an antibody:protein ratio of 26:1) in microsomes from dexamethasone pretreated animals did not reduce the N-hydroxylation of DDS, whereas preincubation with troleandomycin reduced metabolite formation by > or = 50%. Collectively, these data indicate that the constitutive enzymes CYP2C6 and/or CYP2C11, as well as CYP3A1 (nonconstitutive), are capable of catalyzing the hydroxylation of DDS and MADDS.

Acetylcysteine↗
PubMed1997

Metabolism of phencyclidine by human liver microsomes.

These studies examined in vitro metabolism of phencyclidine (PCP) in a series of human liver microsomes (N = 10). Each sample was characterized for cytochrome P450 (CYP) content and for CYP1A, CYP2A, CYP2C, CYP2D, CYP2E, CYP3A, CYP4A, and lauric acid 11-hydroxylation metabolic activities. At least five PCP metabolites (c-PPC, t-PPC, PCHP, an unknown metabolite, and an irreversibly bound metabolite) were formed by the various human liver microsomes. Nevertheless, there was a large degree of inter-individual variation in the metabolite formation. For example, the irreversibly bound metabolite was formed in detectable amounts in only four of the ten samples. c-PPC, t-PPC and the irreversibly bound PCP metabolite formation rates significantly correlated with CYP3A activity. The CYP3A inhibitor troleandomycin was used to inhibit the formation of PCP metabolites. Troleandomycin inhibition was dose dependent with the highest dose producing complete inhibition of the formation of c-PPC, t-PPC, PCHP, and the irreversibly bound metabolite. In addition, PCP inhibited CYP3A-mediated testosterone 6 beta-hydroxylation by 50%. Furthermore, the relative intensity of CYP3A immunoreactive proteins significantly correlated with testosterone 6 beta-hydroxylation and with PCP metabolite formation (except for the unknown metabolite). PCHP formation also correlated with CYP1A activity, while the formation of the unknown PCP metabolite correlated with CYP2A activity. These studies suggest that several CYP isoforms contribute to PCP metabolism and that CYP3A plays a major role in PCP biotransformation in human liver microsomes.

Adult↗
PubMed1997

Oxidation of cyclophosphamide to 4-hydroxycyclophosphamide and deschloroethylcyclophosphamide in human liver microsomes.

We have investigated the formation of 4-hydroxycyclophosphamide (HCY) and deschloroethylcyclophosphamide (DCCY) from cyclophosphamide (CY) in human liver microsomes. For HCY, the estimated values (mean +/- SD; n = 3) of Km1 and Km2 were 0.095 +/- 0.072 and 5.09 +/- 4.30 mM, and the estimated values of Vmax1 and Vmax2 were 0.138 +/- 0.070 and 1.55 +/- 0.50 nmol/min/mg protein. For DCCY, Km1 and Km2 were 0.046 +/- 0.017 and 8.58 +/- 5.84 mM, and Vmax1 and Vmax2 were 0.006 +/- 0.003 and 0.274 +/- 0.214 nmol/min/mg protein. At CY concentrations of 0.1, 0.7, and 5 mM, HCY respectively accounted for 95.7 +/- 1.3, 95.1 +/- 2.4, and 90.7 +/- 2.7% of the total products of CY (HCY + DCCY; n = 6). In a separate experiment, 98.7 +/- 11.9% (n = 3) of CY loss could be accounted for by the formation of HCY at 0.1 mM CY. On the basis of cytochrome P450 (CYP) isoform-specific chemical inhibitor and cDNA-expressed human P450 isozyme studies, CYP2C9 and CYP3A4/5 seemed to be the major P450 isoforms responsible for HCY formation at low (0.1 mM) and high (0.7 and 5 mM) concentrations of CY, respectively. Although orphenadrine inhibition was observed in human liver microsomes (which has been taken to indicate CYP2B6 catalysis), orphenadrine inhibited cDNA-expressed CYP3A4 formation of HCY to the same extent observed in human liver microsomes, and the addition of orphenadrine to incubations containing sulfaphenazole (a specific inhibitor of CYP2C9) or troleandomycin (a specific CYP3A inhibitor) did not increase inhibition beyond that observed with sulfaphenazole or troleandomycin alone. Similar studies indicated that CYP3A4/5 was the major P450 isoform responsible for DCCY formation at high (0.7 and 5 mM) concentrations of CY. The P450 isoform responsible for DCCY formation at 0.1 mM CY could not be identified due to its very low formation rate.

Aryl Hydrocarbon Hydroxylases↗