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PubMed2004

Metabolism of alfentanil by cytochrome p4503a (cyp3a) enzymes.

The synthetic opioid alfentanil is an analgesic and an in vivo probe for hepatic and first-pass CYP3A activity. Alfentanil is a particularly useful CYP3A probe because pupil diameter change is a surrogate for plasma concentrations, thereby affording noninvasive assessment of CYP3A. Alfentanil undergoes extensive CYP3A4 metabolism via two major pathways, forming noralfentanil and N-phenylpropionamide. This investigation evaluated alfentanil metabolism in vitro to noralfentanil and N-phenylpropionamide, by expressed CYP3A5 and CYP3A7 in addition to CYP3A4, with and without coexpressed or exogenous cytochrome b(5). Effects of the CYP3A inhibitors troleandomycin and ketoconazole were also determined. Rates of noralfentanil and N-phenylpropionamide formation by CYP3A4 and 3A5 in the absence of b(5) were generally equivalent, although the metabolite formation ratio differed, whereas those by CYP3A7 were substantially less. CYP3A4 and 3A5 were equipotently inhibited by troleandomycin, whereas ketoconazole was an order of magnitude more potent toward CYP3A4. Cytochrome b(5) qualitatively and quantitatively altered alfentanil metabolism, with b(5) coexpression having a greater effect than exogenous addition. Addition or coexpression of b(5) markedly stimulated the formation of both metabolites and changed the formation of noralfentanil but not N-phenylpropionamide from apparent single-site to multisite Michaelis-Menten kinetics. These results demonstrate that alfentanil is a substrate for CYP3A5 in addition to CYP3A4, and the effects of the CYP3A inhibitors troleandomycin and ketoconazole are CYP3A enzyme-selective. Alfentanil is one of the few CYP3A substrates that is metabolized in vitro as avidly by both CYP3A4 and 3A5. Polymorphic CYP3A5 expression may contribute to inter-individual variability in alfentanil metabolism.

Alfentanil↗
PubMed1989

Effects of clarithromycin on cytochrome P-450. Comparison with other macrolides.

Repeated administration of clarithromycin (0.5 mmol.kg-1 p.o. daily for 5 days) to rats increased markedly the same cytochrome P-450 isoenzyme (P-450p) as that induced by troleandomycin. Clarithromycin, however, did not form cytochrome P-450 Fe(II)-metabolite complexes in vitro with microsomes from clarithromycin-treated rats or in vivo after repeated doses of clarithromycin. Nevertheless, clarithromycin formed cytochrome P-450 Fe(II)-metabolite complexes with microsomes from dexamethasone-treated rats in vitro, or after administration to dexamethasone-treated rats in vivo. Similar effects were observed with roxithromycin. In contrast, erythromycin and troleandomycin formed metabolic complexes when given alone, whereas josamycin, midecamycin and spiramycin did not form complexes, even in dexamethasone-treated rats. We conclude that clarithromycin and roxithromycin induce cytochrome P-450p, but do not form complexes with this isoenzyme, although they do form complexes with other glucocorticoid-inducible isoenzymes. We propose that macrolides may be classified into three groups, those forming complexes when given alone (e.g., erythromycin and troleandomycin), those forming complexes only in glucocorticoid-pretreated rats (clarithromycin and roxithromycin) and those not forming complexes (josamycin, midecamycin and spiramycin).

Animals↗
PubMed1996

The apoprotein of cytochrome P450 3A2 does not selectively direct alkylation to one of four pyrrole rings of N-vinylprotoporphyrin IX.

A variety of porphyrinogenic xenobiotics cause mechanism-based inactivation of a number of rat hepatic cytochrome P450 isozymes. As a result, a mixture of four N-alkylprotoporphyin IX (N-alkylPP) regioisomers, with ferrochelatase-inhibitory properties, are formed. This study was designed to determine whether all four regioisomers are produced on the active site of a single P450 isozyme, or whether the apoprotein of individual P450 isozymes selectively directs the alkylation to one of four pyrrole nitrogen atoms of N-alkylPP. Administration of 3-[2-(2,4,6-trimethylphenyl)thioethyl]-4-methylsydnone (TTMS) to untreated and dexamethasone-pretreated rats results in the formation of four regioisomers of N-vinylprotoporphyrin IX (N-vinylPP). Following coadministration of TTMS with troleandomycin, N-vinylPP formation is reduced to 40 and 43% of control in untreated and dexamethasone-pretreated male rats. Since troleandomycin is a selective inhibitor of rat hepatic P450 3A, the difference in N-vinylPP regioisomer formation between control (TTMS alone) and TTMS plus troleandomycin coadministered rats represents the difference due to P450 3A. This allowed us to calculate that all four regioisomers of N-vinylPP are formed by P450 3A isozymes in both untreated and dexamethasone-pretreated male rats. Since untreated male rats express P450 3A2, but not P450 3A1, we conclude that the apoprotein of rat hepatic P450 3A2 does not selectively direct the alkylation to one of four pyrrole nitrogens of N-vinylPP.

Alkylation↗
PubMedDate not supplied

A further interaction study of quinine with clinically important drugs by human liver microsomes: determinations of inhibition constant (Ki) and type of inhibition.

Our previous study showed that several drugs inhibited quinine 3-hydroxylation, a cytochrome P450 (CYP) 3A4-mediated reaction, in vitro. In this extended study, 13 drugs were selected and tested by human liver microsomes in order to further determine their respective inhibition constant (Ki) and type of inhibition. According to the apparent Ki values, the inhibitory rank order of these tested drugs was as follows: ketoconazole > doxycycline > omeprazole > tetracycline > troleandomycin (with pre-incubation) > primaquine > troleandomycin (without pre-incubation) > nifedipine > erythromycin > verapamil > oleandomycin > diltiazem > cimetidine > hydralazine. Among these drugs, doxycycline, tetracycline, ketoconazole, nifedipine and hydralazine were judged as mixed inhibitors; whereas, the remaining other drugs tested were judged as competitive inhibitors. When the plasma/serum concentrations possibly attained after their usual therapeutic doses were taken into account, tetracycline, doxycycline, omeprazole, ketoconazole, nifedipine, troleandomycin and erythromycin are likely to be inhibitors of quinine metabolism in patients when these drugs are co-administrated with quinine.

Calcium Channel Blockers↗
PubMed1990

Reconstitution of testosterone oxidation by purified rat cytochrome P450p (IIIA1).

Cytochrome P450p (IIIA1) has been purified from rat liver microsomes by several investigators, but in all cases the purified protein, in contrast to other P450 enzymes, has not been catalytically active when reconstituted with NADPH-cytochrome P450 reductase and dilauroylphosphatidylcholine. We now report the successful reconstitution of testosterone oxidation by cytochrome P450p, which was purified from liver microsomes from troleandomycin-treated rats. The rate of testosterone oxidation was greatest when purified cytochrome P450p (50 pmol/ml) was reconstituted with a fivefold molar excess of NADPH-cytochrome P450 reductase, an equimolar amount of cytochrome b5, 200 micrograms/ml of a chloroform/methanol extract of microsomal lipid (which could not be substituted with dilauroylphosphatidylcholine), and the nonionic detergent, Emulgen 911 (50 micrograms/ml). Testosterone oxidation by cytochrome P450p was optimal at 200 mM potassium phosphate, pH 7.25. In addition to their final concentration, the order of addition of these components was found to influence the catalytic activity of cytochrome P450p. Under these experimental conditions, purified cytochrome P450p converted testosterone to four major and four minor metabolites at an overall rate of 18 nmol/nmol P450p/min (which is comparable to the rate of testosterone oxidation catalyzed by other purified forms of rat liver cytochrome P450). The four major metabolites were 6 beta-hydroxytestosterone (51%), 2 beta-hydroxytestosterone (18%), 15 beta-hydroxytestosterone (11%) and 6-dehydrotestosterone (10%). The four minor metabolites were 18-hydroxytestosterone (3%), 1 beta-hydroxytestosterone (3%), 16 beta-hydroxytestosterone (2%), and androstenedione (2%). With the exception of 16 beta-hydroxytestosterone and androstenedione, the conversion of testosterone to each of these metabolites was inhibited greater than 85% when liver microsomes from various sources were incubated with rabbit polyclonal antibody against cytochrome P450p. This antibody, which recognized two electrophoretically distinct proteins in liver microsomes from troleandomycin-treated rats, did not inhibit testosterone oxidation by cytochromes P450a, P450b, P450h, or P450m. The catalytic turnover of microsomal cytochrome P450p was estimated from the increase in testosterone oxidation and the apparent increase in cytochrome P450 concentration following treatment of liver microsomes from troleandomycin- or erythromycin-induced rats with potassium ferricyanide (which dissociates the cytochrome P450p-inducer complex). Based on this estimate, the catalytic turnover values for purified, reconstituted cytochrome P450p were 4.2 to 4.6 times greater than the rate catalyzed by microsomal cytochrome P450p.

Animals↗
PubMed2004

Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone.

BACKGROUND: The disposition of the long-acting opioid methadone, used to prevent opiate withdrawal and treat short- and long-lasting pain, is highly variable. Methadone undergoes N -demethylation to the primary metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP), catalyzed in vitro by intestinal, hepatic, and expressed cytochrome P450 (CYP) 3A4. However, the role of CYP3A4 in human methadone disposition in vivo is unclear. This investigation tested the hypothesis that CYP3A induction (or inhibition) would increase (or decrease) methadone metabolism and clearance in humans. METHODS: Healthy volunteers were studied in a randomized, balanced, 4-way crossover study. They received intravenous (IV) midazolam (to assess CYP3A4 activity) and then simultaneous oral deuterium-labeled and IV unlabeled methadone after pretreatment with rifampin (INN, rifampicin) (hepatic/intestinal CYP3A induction), troleandomycin (hepatic/intestinal CYP3A inhibition), grapefruit juice (selective intestinal CYP3A inhibition), or nothing. Methadone effects were measured by dark-adapted pupil diameter. CYP isoforms catalyzing methadone metabolism by human liver microsomes and expressed CYPs in vitro were also evaluated. RESULTS: Methadone had high oral bioavailability (70%) and low intestinal (22%) and hepatic (9%) extraction, and there was a significant correlation ( r = 0.94, P <.001) between oral bioavailability and intestinal (but not hepatic) availability. Rifampin decreased bioavailability and oral and IV methadone plasma concentrations and increased IV clearance (4.42 +/- 1.00 mL. kg -1. min -1 versus 1.61 +/- 0.67 mL. kg -1. min -1, P <.05) and oral clearance (8.50 +/- 3.68 mL. kg -1. min -1 versus 2.05 +/- 0.92 mL. kg -1. min -1, P <.05), EDDP/methadone area under the curve (AUC) ratios, EDDP formation clearances, and hepatic extraction (0.27 +/- 0.06 versus 0.09 +/- 0.04, P <.05). Troleandomycin and grapefruit juice decreased the EDDP/methadone AUC ratio after oral methadone (0.17 +/- 0.10 and 0.14 +/- 0.06 versus 0.27 +/- 0.20, P <.05) but not IV methadone and had no effect on methadone plasma concentrations, IV clearance (1.29 +/- 0.41 mL. kg -1. min -1 and 1.48 +/- 0.55 mL. kg -1. min -1 ) or oral clearance (2.05 +/- 1.52 mL. kg -1. min -1 and 1.89 +/- 1.07 mL. kg -1. min -1 ), or other kinetic parameters. There was no correlation between methadone clearance and hepatic CYP3A4 activity. Pupil diameter changes reflected plasma methadone concentrations. In vitro experiments showed a predominant role for both CYP3A4 and CYP2B6 in liver microsomal methadone N -demethylation. CONCLUSION: First-pass intestinal metabolism is a determinant of methadone bioavailability. Intestinal and hepatic CYP3A activity only slightly affects human methadone N -demethylation but has no significant effect on methadone concentrations, clearance, or clinical effects. Greater rifampin effects, compared with troleandomycin and grapefruit juice, on methadone disposition suggest a major role for intestinal transporters and for other CYPs, such as CYP2B6. Interindividual variability and drug interactions affecting intestinal transporter and hepatic CYP3A and CYP2B6 activity may alter methadone disposition.

Adult↗
PubMed2000

Resveratrol, a red wine constituent, is a mechanism-based inactivator of cytochrome P450 3A4.

Resveratrol, a phytoalexin found in red wine, has been shown to possess antioxidant and antimutagenic properties. Incubation of resveratrol with Sf9 insect microsomes containing baculovirus-derived human cytochrome P450 3A4 (CYP3A4) and NADPH-cytochrome P450 reductase showed that resveratrol inactivated CYP3A4 in a time- and NADPH-dependent manner. Resveratrol, erythromycin and troleandomycin inactivated CYP3A4 at a similar rate (as reflected by k(inact)) whereas the binding affinity to CYP3A4 (as reflected by K(I)) was in the order of: troleandomycin > erythromycin > resveratrol. (K(I) and k(inact) for CYP3A4 inactivation by resveratrol, erythromycin and troleandomycin are 20 microM and 0.20 min(-1), 5.3 microM and 0.12 min(-1) and 0.18 microM and 0.15 min(-1), respectively.) Fractionation studies of red wine showed that fractions that did not contain resveratrol inactivated CYP3A4 significantly. In addition, the resveratrol content in red wine used in the study was too low to account for the degree of CYP3A4 inactivation observed after red wine treatment. Inactivation studies using a variety of red wine types showed that the CYP3A4 inactivation did not correlate to their resveratrol content. In summary, data here showed that resveratrol is an effective mechanism-based inactivator of CYP3A4; however, it is not one of the main red wine constituents that are responsible for CYP3A4 inactivation by red wine. Nevertheless, inactivation of CYP3A4 by resveratrol may cause clinically relevant drug interactions with CYP3A4 substrates.

Animals↗
PubMed2005

Evaluation of time-dependent inactivation of CYP3A in cryopreserved human hepatocytes.

Irreversible CYP3A inhibition by drugs constitutes one of the major causes of inhibition-based drug interactions. We evaluated time-dependent inactivation of CYP3A in cryopreserved human hepatocytes for six structurally diverse compounds known to exhibit this property. Inactivation kinetic parameters were also determined using human liver microsomes. Except for diclofenac, which did not cause CYP3A inactivation either in microsomes or in hepatocytes at concentrations up to 100 microM, time-dependent inactivation was observed in hepatocytes for amprenavir, diltiazem, erythromycin, raloxifene, and troleandomycin. The observed inactivation potency in hepatocytes (observed IC50) was compared with the potency predicted using microsomal parameters (predicted IC50). Despite satisfactory prediction for troleandomycin (1.35 and 2.14 microM for the predicted and observed IC50, respectively), over-prediction of inactivation was observed for raloxifene, amprenavir, and erythromycin (observed IC50 values 6.2-, 55-, and 7.8-fold higher, respectively, than the predicted IC50). By contrast, the observed IC50 for diltiazem in hepatocytes was approximately 4-fold lower than the IC50 predicted from microsomal data (under-prediction). After correcting for factors including nonspecific binding and inactivator consumption, prediction was significantly improved for raloxifene (the observed IC50 then became 2-fold higher than the predicted IC50) and for amprenavir to a lesser extent. A specific P-glycoprotein inhibitor, 4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)-N-[2-(3.4-dimethoxyphenyl)ethyl]-6,7-dimethoxyquinazolin-2-amine (CP-100356), modulated the observed CYP3A inactivation potency by erythromycin and troleandomycin. In summary, these studies reveal three important factors that must be considered when microsomal inactivation parameters are used to predict inhibition-based drug interactions in intact cell systems.

Cryopreservation↗
PubMed1992

Pharmacokinetic drug interactions of macrolides.

The macrolide antibiotics include natural members, prodrugs and semisynthetic derivatives. These drugs are indicated in a variety of infections and are often combined with other drug therapies, thus creating the potential for pharmacokinetic interactions. Macrolides can both inhibit drug metabolism in the liver by complex formation and inactivation of microsomal drug oxidising enzymes and also interfere with microorganisms of the enteric flora through their antibiotic effects. Over the past 20 years, a number of reports have incriminated macrolides as a potential source of clinically severe drug interactions. However, differences have been found between the various macrolides in this regard and not all macrolides are responsible for drug interactions. With the recent advent of many semisynthetic macrolide antibiotics it is now evident that they may be classified into 3 different groups in causing drug interactions. The first group (e.g. troleandomycin, erythromycins) are those prone to forming nitrosoalkanes and the consequent formation of inactive cytochrome P450-metabolite complexes. The second group (e.g. josamycin, flurithromycin, roxithromycin, clarithromycin, miocamycin and midecamycin) form complexes to a lesser extent and rarely produce drug interactions. The last group (e.g. spiramycin, rokitamycin, dirithromycin and azithromycin) do not inactivate cytochrome P450 and are unable to modify the pharmacokinetics of other compounds. It appears that 2 structural factors are important for a macrolide antibiotic to lead to the induction of cytochrome P450 and the formation in vivo or in vitro of an inhibitory cytochrome P450-iron-nitrosoalkane metabolite complex: the presence in the macrolide molecules of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the drug. Troleandomycin ranks first as a potent inhibitor of microsomal liver enzymes, causing a significant decrease of the metabolism of methylprednisolone, theophylline, carbamazepine, phenazone (antipyrine) and triazolam. Troleandomycin can cause ergotism in patients receiving ergot alkaloids and cholestatic jaundice in those taking oral contraceptives. Erythromycin and its different prodrugs appear to be less potent inhibitors of drug metabolism. Case reports and controlled studies have, however, shown that erythromycins may interact with theophylline, carbamazepine, methylprednisolone, warfarin, cyclosporin, triazolam, midazolam, alfentanil, disopyramide and bromocriptine, decreasing drug clearance. The bioavailability of digoxin appears also to be increased by erythromycin in patients excreting high amounts of reduced digoxin metabolites, probably due to destruction of enteric flora responsible for the formation of these compounds. These incriminated macrolide antibiotics should not be administered concomitantly with other drugs known to be affected metabolically by them, or at the very least, combined administration should be carried out only with careful patient monitoring.(ABSTRACT TRUNCATED AT 400 WORDS)

Anti-Bacterial Agents↗
PubMedDate not supplied

Lack of effect of streptogramins on hepatic drug metabolism enzymes in the rat.

Male Sprague-Dawley rats were treated with streptogramin derivatives (RP 7293, RP 54476, RP 57669, and RP 59500) or with the macrolide troleandomycin. Liver cytosol and microsomes were prepared, and the in vitro transformation of several model substrates studied. Furthermore, total and complexed microsomal cytochrome P-450 levels were compared. Hepatic cytochrome P-450 metabolite complexes were detected 4 days after troleandomycin treatment (500 mg/kg/day po), whereas such effects were not observed with po RP 7293 (500 mg/kg/day, 4 days) or with iv RP 54476 (12 mg/kg/day, 7 days), RP 57669 (6 mg/kg/day, 7 days), or RP 59500 (6 and 18 mg/kg/day, 7 days). The administration of troleandomycin resulted in statistically significant increases in liver weight (+20%), microsomal protein (+70%), total cytochrome P-450 (+187%), and cytosolic glutathione S-transferase activity (+32%). The activities of aniline hydroxylase, aminopyrine N-demethylase, and the high and low phases of 7-ethoxyresorufin O-deethylase were markedly decreased by 36% to 56%. In contrast, none of these hepatic parameters was changed significantly after administration of each streptogramin. These results suggest that streptogramins have not, in contrast to many commonly used macrolide antibiotics, had potent or specific effects on hepatic drug metabolizing enzymes in rats.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1989

[Comparative in vitro bacteriostatic and bactericidal effect of 5 macrolides: roxithromycin, erythromycin, oleandomycin, josamycin and spiramycin against 284 hospital bacterial strains].

The bacteriostatic and bactericidal activities of five macrolides (roxithromycin, erythromycin, troleandomycin, josamycin and spiramycin) were tested against 284 bacterial strains belonging to various species of Gram positive (staphylococci, streptococci, pneumococci, Listeria sp, Corynebacterium sp, Bacillus sp) and Gram negative bacteria (Neisseria sp, H. influenzae, P. multocida). The activity of these compounds on the whole strains showed near results: 71.8% of susceptible strains to erythromycin and spiramycin, 70% to josamycin, 67.6% to roxithromycin, 65.5% to troleandomycin. Resisting strains were MLSB resistant cocci Gram positive, H. influenzae and P. multocida strains. Species usually less studied (nongroupable streptococci, Corynebacterium sp, Bacillus sp) were very susceptible to macrolides with MICS equal or inferior to 1 mg/l for the two last genus. A bactericidal effect was observed for 38.8% of 72 tested strains (erythromycin), 36.1% (josamycin), 34.7% (spiramycin), 31.9% (roxithromycin), 20.8% (troleandomycin). Among various tested species, this bactericidal effect concerned especially group A streptococci, N. meningitidis and Corynebacterium (except D2 and JK species).

Cross Infection↗
PubMed1995

Enhanced rates of cytochrome P450 metabolic-intermediate complex formation from nonmacrolide amines in rifampicin-treated rabbit liver microsomes.

The formation of cytochrome P450 metabolic-intermediate (MI) complexes from amine-containing drugs unrelated to macrolide antibiotics was investigated in hepatic microsomes from rifampicin-induced rabbits. Rifampicin treatment doubled the amount of total cytochrome P450 present. As evidenced by increased rates of erythromycin N-demethylation and MI complex formation from troleandomycin without increases in other isozyme selective oxidation reactions, the increase was predominately in the cytochrome P4503A subfamily. Fluoxetine, benzylamphetamine, propoxyphene, and norpropoxyphene formed MI complexes at rates similar to that for troleandomycin. Rates for 1-alpha-acetylmethadol and SKF 525A were 2- to 3-fold higher, and rates for the secondary amine derivatives of these two compounds, nor-1-alpha-acetylmethadol and SKF 8742A, were approximately 5-fold higher than with troleandomycin. For the SKF and acetylmethadol compounds, the rates were much higher in rifampicin-induced microsomes, compared with phenobarbital-induced microsomes. MI complex formation from benzylamphetamine was the reverse. The rate of MI complex formation from benzylamphetamine in phenobarbital-induced microsomes was similar to that from SKF 8742A and nor-1-alpha-acetylmethadol in microsomes from rabbits treated with the highest dose of rifampicin. Cytochrome P450 MI complex formation from all compounds was either low or absent from microsomes of vehicle-treated animals.

Amines↗
PubMedDate not supplied

Human halothane metabolism, lipid peroxidation, and cytochromes P(450)2A6 and P(450)3A4.

OBJECTIVE: Halothane undergoes both oxidative and reductive metabolism by cytochrome P450 (CYP), respectively causing rare immune-mediated hepatic necrosis and common, mild subclinical hepatic toxicity. Halothane also causes lipid peroxidation in rodents in vitro and in vivo, but in vivo effects in humans are unknown. In vitro investigations have identified a role for human CYPs 2E1 and 2A6 in oxidation and CYPs 2A6 and 3A4 in reduction. The mechanism-based CYP2E1 inhibitor disulfiram diminished human halothane oxidation in vivo. This investigation tested the hypotheses that halothane causes lipid peroxidation in humans in vivo, and that CYP2A6 or CYP3A4 inhibition can diminish halothane metabolism. METHODS: Patients (n = 9 each group) received single doses of the mechanism-based inhibitors troleandomycin (CYP3A4), methoxsalen (CYP2A6) or nothing (controls) before a standard halothane anaesthetic. Reductive halothane metabolites chlorotrifluoroethane and chlorodifluoroethylene in exhaled breath, fluoride in urine, and oxidative metabolites trifluoroacetic acid and bromide in urine were measured for 48 h postoperatively. Lipid peroxidation was assessed by plasma F2-isoprostane concentrations. RESULTS: The halothane dose was similar in all groups. Methoxsalen decreased 0- to 8-h trifluoroacetic acid (23 +/- 20 micromol vs 116 +/- 78 micromol) and bromide (17 +/- 11 micromol vs 53 +/- 49 micromol) excretion (P < 0.05), but not thereafter. Plasma F2-isoprostanes in controls were increased from 8.5 +/- 4.5 pg/ml to 12.5 +/- 5.0 pg/ml postoperatively (P < 0.05). Neither methoxsalen nor troleandomycin diminished reductive halothane metabolite or F2-isoprostane concentrations. CONCLUSIONS: These results provide the first evidence for halothane-dependent lipid peroxidation in humans. Methoxsalen effects on halothane oxidation confirm in vitro results and suggest limited CYP2A6 participation in vivo. CYP2A6-mediated, like CYP2E1-mediated human halothane oxidation, can be inhibited in vivo by mechanism-based CYP inhibitors. In contrast, clinical halothane reduction and lipid peroxidation were not amenable to suppression by CYP inhibitors.

Adult↗
PubMed1986

Digitoxin metabolism by liver microsomal cytochrome P-450 and UDP-glucuronosyltransferase and its role in the protection of rats from digitoxin toxicity by pregnenolone-16 alpha-carbonitrile.

The aim of the present study was to investigate whether the mechanism by which pregnenolone-16 alpha-carbonitrile (PCN) protects rats from digitoxin toxicity was dependent on the induction of liver microsomal cytochrome P-450p and/or the UDP-glucuronosyltransferase active toward digitoxigenin monodigitoxoside (UDP-GT-dt1). Evidence is presented that suggests troleandomycin is a selective inhibitor of cytochrome P-450p in vivo, based on the pattern of inhibition observed when zoxazolamine paralysis time and hexobarbital sleeping time were measured in rats treated with different cytochrome P-450 inducers. A single dose of troleandomycin completely reversed the ability of PCN to protect rats from digitoxin toxicity, establishing the importance of cytochrome P-450p induction in the protective effect of PCN. The postpubertal decline in constitutive cytochrome P-450p levels in female but not male rats was paralleled by a female-specific, age-dependent decline in the rate of digitoxin sugar cleavage (i.e., digitoxosyl oxidation of digitoxin to 15'-dehydrodigitoxin and digitoxosyl cleavage to digitoxigenin bisdigitoxoside). This resulted in a marked sex difference in the rate of digitoxin sugar cleavage catalyzed by liver microsomes from mature rats (male/female approximately 6). However, no sex difference in digitoxin toxicity was observed in either immature or mature rats. In contrast to cytochrome P-450p, liver microsomal UDP-GT-dt1 activity increased dramatically with age in both male and female rats (mature/immature approximately 10). However, no age differences in digitoxin toxicity were observed in rats of either sex. The results indicate that cytochrome P-450p and UDP-GT-dt1 can be independently regulated in rat liver and that large changes in the constitutive levels of these microsomal enzymes have no effect on digitoxin toxicity. This suggests that the induction of cytochrome P-450p and UDP-GT-dt1 does not fully account for the mechanism by which PCN protects rats from digitoxin toxicity.

Age Factors↗
PubMed1983

Dual effects of macrolide antibiotics on rat liver cytochrome P-450. Induction and formation of metabolite-complexes: a structure-activity relationship.

Previous studies have shown that the macrolide antibiotics, troleandomycin and erythromycin, are able to induce their own transformation into a metabolite forming an inactivated complex with rat liver cytochrome P-450. This paper reports the results of a study on the effects of several macrolide antibiotics including oleandomycin, erythromycin derivatives, josamycin, methymycin, tylosin, spiramycin and rifampicin, as well as antibiotics of other series, such as tetracycline and lincomycin, on rat liver cytochromes P-450 in vivo and in vitro. Only the antibiotics containing the desosamine and mycaminose amino sugars were able to give the dual effects already found with troleandomycin: induction of cytochrome p-450 and formation of an inhibitory cytochrome P-450--iron--nitrosoalkane metabolite complex in vivo or in vitro. From these studies, it appears that two structural factors are important for a macrolide antibiotic to lead to such effects: the presence of a non-hindered readily accessible N-dimethylamino group and the hydrophobic character of the molecule. These data are discussed in relation to the adverse effects observed during drug associations involving some of these macrolide antibiotics.

Animals↗
PubMed1987

Studies on the pregnenolone-16 alpha-carbonitrile-inducible form of rat liver microsomal cytochrome P-450 and UDP-glucuronosyltransferase.

Treatment of rats with pregnenolone-16 alpha-carbonitrile (PCN) markedly induces rat liver microsomal cytochrome P-450p and UDP-GT-dt1, a glucuronosyltransferase active towards the digitoxin metabolite, digitoxigenin monodigitoxoside. The present study characterizes the regulation of these two enzymes in rats treated with different xenobiotics. Like PCN, treatment of rats with dexamethasone, spironolactone, troleandomycin or erythromycin estolate markedly induced both UDP-GT-dt1 and cytochrome P-450p (measured as erythromycin demethylase and testosterone 2 beta-, 6 beta-, 15 beta-, and 18-hydroxylase activities). However, compared to PCN and dexamethasone, both troleandomycin and erythromycin estolate preferentially induced cytochrome P-450p, whereas spironolactone preferentially induced UDP-GT-dt1. Treatment of rats with the polychlorinated biphenyl mixture, Aroclor 1254, increased both cytochrome P-450p and UDP-GT-dt1 activity to about 40% of that in liver microsomes from rats induced with PCN or dexamethasone. Treatment of rats with phenobarbital or chlordane caused a relatively small increase in cytochrome P-450p and UDP-GT-dt1 activity. Neither enzyme was induced by treatment of rats with 3-methylcholanthrene, rifampin or digitoxin. The induction of cytochrome P-450p and UDP-GT-dt1 by PCN followed similar dose-response curves. Although cytochrome P-450p and UDP-GT-dt1 are differentially affected by the age and the sex of rats, the enzymes responded similarly, but not identically, to xenobiotic treatment. This suggests that cytochrome P-450p and UDP-GT-dt1 are co-inducible but not coordinately regulated.

Animals↗
PubMed1993

Simple methods for the qualitative identification and quantitative determination of macrolide antibiotics.

Pyrolysis-gas chromatography is shown to be a rapid straightforward method for the qualitative differentiation of the macrolide antibiotics erythromycin, oleandomycin, troleandomycin, spiramycin and tylosin. Organic salts do not interfere and identification of erythromycin and troleandomycin in commercial products is viable. Spectrophotometric quantitation of these same five antibiotics after reaction with concentrated sulphuric acid is studied at about 470 nm. Reaction conditions such as acid concentration, time and temperature are provided. The sugar moieties of the antibiotics are proposed as the reactive sites. Detection limits are about 0.2-1.0 microg ml-1 [corrected] and analysis of pharmaceutical products should be possible.

Anti-Bacterial Agents↗
PubMed2002

Paraquat detoxicative system in the mouse liver postmitochondrial fraction.

We examined the paraquat detoxicative system in mouse livers. The survival rate of mice receiving 50 mg/kg paraquat was 41% at 7 days and significantly rose to 88, 64, 69% with pretreatment with phenytoin, phenobarbital, and rifampicin, respectively. Phenytoin induced activity in NADPH-cytochrome P450 reductase, CYP3A, CYP2B, and CYP2C that was 3 to 4 times higher than that of the controls. Phenobarbital induced CYP2B and rifampicin induced CYP3A, respectively, in addition to NADPH-cytochrome P450 reductase. 3-Methylcholanthrene did not induce these enzymes and did not alter the survival rate. All the mice pretreated with CoCl(2) (a CYP synthesis inhibitor) or SKF 525-A (a CYP inhibitor) were dead after 5 days, and troleandomycin (a CYP3A-specific inhibitor) also reduced the survival rate. When cell homogenates were incubated with paraquat and NADPH, paraquat decreased and its metabolic intermediate paraquat-monopyridone was formed. Troleandomycin inhibited the decrease in paraquat and increased the monopyridone. After making a subfraction of the homogenate, monopyridone was produced in the postmicrosomal 105,000g supernatant, but not in the microsomes. The pretreatment of mice with phenytoin decreased the monopyridone in the postmitochondrial fraction, but did not affect the supernatant. These results indicated that paraquat was first metabolized in the postmicrosomal supernatant into monopyridone, and that may have been subsequently hydroxylated by the microsomes. Repeated intravenous injections of alpha-tocopherol to paraquat-loaded mice significantly reduced the paraquat mortality and when these mice were pretreated with rifampicin, 100% of them survived. These studies demonstrate that postmitochondrial fractions play an important role in paraquat detoxication metabolism, and that the combination of CYP induction and alpha-tocopherol administration is highly useful for the survival of paraquat-exposed mice.

Animals↗