Species differences in the disposition and metabolism of sulfinpyrazone

1. The disposition and metabolism of sulfinpyrazone have been studied in rats, guineapigs, rabbits, dogs, rhesus monkeys and miniature swine after intravenous administration of 100mg/kg of ¹⁴C-labelled drug.

2. In all species, the integrated plasma concentration (AUC, 0-24h) of total radioactivity was almost completely covered by the sum of the AUC-values of unchanged sulfinpyrazone and six metabolites, i.e. the sulphide, the sulphone, p-hydroxy-sulfinpyrazone, the p-hydroxy-sulphide, the p-hydroxy-sulphone and 4-hydroxy-sulfinpyrazone.

3. Comparison of the plasma level profiles of unchanged sulfinpyrazone and the metabolites revealed pronounced differences between the species. Unchanged sulfinpyrazone was the most prominent compound in plasma of rats, dogs, monkeys and swine, whereas the sulphide metabolite predominated in guinea-pigs. In plasma of rabbits, these two compounds were found in similar amounts.

4. Species with predominant renal excretion of the ¹⁴C dose, i.e. rabbits, dogs and monkeys, eliminated sulfinpyrazone to a high extent unchanged. The renal excretion of the sulphide metabolite was low in all species.

5. Species differences in the biotransformation of sulfinpyrazone explain previously observed differences in inhibitory effect on platelet aggregation. This effect is intensive and long-lasting in species showing high plasma concentrations of the sulphide metabolite.     

Species differences in the disposition and metabolism of camazepam

1. After i.v. injection of camazepam, plasma camazepan concn. declined biexponentially. The half-life of the elimination phase (t_{1/2, β}) increased in the order: mice (0.73?h), rats (1.3?h), dogs (5.3?h).

2. After oral dosing of camazepam, absorption was almost complete whereas systemic availability varied eight-fold, i.e., rats and mice (10.15%) < dogs and monkeys (about 60%) < humans (> 90%), indicating species difference in the first-pass effect.

3. Camazepam was metabolized extensively in all species investigated to more than 10 metabolites, which were desmethyl, descarbamoyl and/or hydroxy products.

4. In comparison with camazepam, plasma concn. of pharmacologically active metabolites, temazepam, oxazepan and hydroxy camazepam, were much higher in rats and mice than in dogs and monkeys.     

Species differences in the disposition and metabolism of camazepam

After i.v. injection of camazepam, plasma camazepan concn. declined biexponentially. The half-life of the elimination phase (t1/2, beta) increased in the order: mice (0.73 h), rats (1.3 h), dogs (5.3 h). After oral dosing of camazepam, absorption was almost complete whereas systemic availability varied eight-fold, i.e., rats and mice (10-15%) less than dogs and monkeys (about 60%) less than humans (greater than 90%), indicating species difference in the first-pass effect. Camazepam was metabolized extensively in all species investigated to more than 10 metabolites, which were desmethyl, descarbamoyl and/or hydroxy products. In comparison with camazepam, plasma concn. of pharmacologically active metabolites, temazepam, oxazepan and hydroxy camazepam, were much higher in rats and mice than in dogs and monkeys.     

Species differences in the formation of butadiene monoxide from 1,3-butadiene

When 1,3-butadiene is incubated with liver postmitochondrial fractions from mouse, rat, monkey or man and a NADPH-regenerating system, the formation rate of butadiene monoxide is different in the four species. With the exception of the rhesus monkey, the amount of epoxide is proportional to the monooxygenase activity. The sequence of epoxide formation is B6C3F₁ mouse, Sprague Dawley rat, man, rhesus monkey. The ratio between mouse and monkey was about 71. When 1,3-butadiene is incubated with homogenates from lung tissue, only tissues from mouse and rat produce measurable butadiene monoxide concentrations. The monooxygenase activity in lung tissue of the mouse was only 1/30 that in mouse liver. By contrast, lung tissue formed epoxide concentrations comparable to those formed by liver tissue, whereas monkey and human lung tissue did not produce any measurable levels of butadiene monoxide. The data might suggest that the results of recent rodent inhalation studies with 1,3-butadiene could not automatically be extrapolated to man.     

Species differences in disposition of benzo[a]pyrene

Comparison of disposition of benzo[a]pyrene (B[a]P) among Sprague-Dawley rats, Gunn rats, hamsters, and guinea pigs was performed. [3H]B[a]P was administered intratracheally to animals, and the rate of excretion of radioactivity into bile, types of metabolites of B[a]P in bile, and distribution of radioactivity among tissues were determined. In Sprague-Dawley rats, Gunn rats, and guinea pigs, the rate of excretion of radioactivity was dependent upon the administered dose. Excretion and tissue distribution of radioactivity were qualitatively similar among these species although quantitative differences were observed. In hamsters, the rate of excretion was essentially independent of dose at the concentrations examined (0.16 and 350 micrograms). The major difference between hamsters and the other species was that increased amounts of radioactivity were retained in lungs of hamsters at the lower dose with a proportional decrease in the amount of radioactivity excreted into bile. The types and relative amounts of conjugated and nonconjugated metabolites of B[a]P were similar in bile of Sprague-Dawley rats and hamsters. Smaller amounts of glucuronides and larger amounts of sulfate conjugates were detected in bile of Gunn rats than in bile of Sprague-Dawley rats or hamsters. Metabolites in bile of guinea pigs were markedly different from those in the other species in that approximately 90% of the metabolites were thioether conjugates. Buthionine sulfoxime was used to reduce tissue levels of glutathione in Sprague-Dawley rats. When liver and lung glutathione levels were reduced to 30% and 82% of control levels, respectively, the amount of radioactivity excreted into bile was not significantly different from controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Species differences in butadiene metabolism between mice and rats evaluated by inhalation pharmacokinetics

Metabolism of 1,3-butadiene to 1,2-epoxybutene-3 in rats follows saturation kinetics. Comparative investigation of inhalation pharmacokinetics in mice also revealed a saturation pattern. For both species linear pharmacokinetics apply at exposure concentrations below 1000 ppm 1,3-butadiene; saturation of butadiene metabolism is observed at atmospheric concentrations of about 2000 ppm.For mice metabolic clearance per kg body weight in the lower concentration range where first order metabolism applies was 7300ml×h^–1 (rat: 4500 ml×h^–1). Maximal metabolic elimination rate (V_max) was 400 mol×h^–1 ×kg^–1 (rat: 220 mol ×h^–1×kg^–1). This shows that 1,3-butadiene is metabolized by mice at higher rates compared to rats.Based on these investigations, the metabolic elimination rates of butadiene in both species were calculated for the exposure concentrations applied in two inhalation bioassays with rats and with mice. The results show that the higher rate of butadiene metabolism in mice when compared to rats may only in part be responsible for the considerable difference in the susceptibility of both species to butadiene-induced carcinogenesis.     

Species differences in release of arachidonate metabolites in response to inhaled diluted diesel exhaust

In life-span studies in CD-1 mice and F344/Crl rats, inhaled diluted diesel exhaust was highly fibrogenic in rats but not in mice. This was the case despite the higher lung burden, in mg soot/g lung, achieved in mice compared to rats. We tested the hypothesis that the greater fibrogenicity of the soot in rats was due in part to greater release of mediators of inflammation from alveolar cells in rats compared to mice. Female F344/rats and B6C3F1 mice were exposed for up to 17 days to diluted diesel exhaust containing 3.5 mg/m3 of soot. The lungs of control and soot-exposed animals were lavaged after 2, 12 or 17 days of exposure. The presence of leukotriene (LT)B4, LTC4, prostaglandin (PG)E2, PGF2 alpha and thromboxane (TX) B2 in the lavage fluids and LTB4 and PGF2 alpha in cultured lavage cell supernatants was determined. The total amount of each lavage fluid constituent was normalized to lung weight for species comparisons. Control rats had higher levels of TXB2 (16-fold), and LTB4 (6-fold) and PGE2 (2-fold) than control mice, but control mice had higher amounts of LTC4 (4-fold). Control rats and mice had approximately the same amounts of PGF2 alpha/g lung in bronchoalveolar lavage fluid (BALF). Rats exposed to diesel exhaust had increases in BALF PGF2 alpha and LTB4 that were highest after 2 days of exposure and decreased thereafter. Mice had lesser increases in both parameters. Rat cells recovered from lavage fluid released larger amounts of LTB4 into culture supernatants than mouse cells. The data were consistent with the hypothesis that soot-laden rat alveolar cells release greater quantities of mediators of inflammation than do the alveolar cells in mice.     

The disposition of inhaled lysine theophylline in volunteers

Summary Six healthy volunteers received an iv infusion of 317 mg lysine theophylline (equivalent to 197 mg anhydrous theophylline) in order to calculate theophylline clearance by standard methods. They subsequently received a 20 minute inhalation of nebulised lysine theophylline. Serum and salivary theophylline concentrations were measured and all saliva was collected for the first hour. From these concentrations estimates were made of the distribution of theophylline into the blood and saliva with 40% to 94% identified in the blood. Very high salivary concentrations were reached during the inhalation phase with saliva: serum concentration ratios of between 60 and 1600.     

Gender differences in the disposition of metronidazole

OBJECTIVE: Gender is usually considered to be one of the factors influencing disposition of drugs, but the evidence available is sometimes conflicting and information for a large number of frequently used drugs is lacking. An evaluation of sex differences in the disposition ofmetronidazole was carried out during a bioequivalence study. SUBJECTS AND METHODS: Twenty-four volunteers (12 males and 12 females) were included in an open, single-dose, two-sequence, crossover randomized trial with a one-week washout interval. All volunteers received in each period, a single 250 mg dose of one of the two study formulations of metronidazole. Venous blood samples were collected immediately before and at 15 time points in an 48-hour interval after drug administration; metronidazole concentrations were determined by HPLC. Non-compartmental pharmacokinetic analysis was performed and log-transformed AUC(0-infinity) and Cmax were tested for bioequivalence. Sex differences were evaluated by means of a 4-factor (sex, sequence, treatment and period) ANOVA. RESULTS: The studied formulations were found bioequivalent according to international standards: average 90% confidence interval for AUC(0-infinity) was 98 to 104 and for Cmax 93 to 115. After correction for the administered dose/kg, AUC was about 12% lower in females than in males (p = 0.0388) and, therefore, a higher calculated oral Cl/kg was found in females. Apparent distribution volume, after correction for weight, was significantly higher in males (p = 0.0019). Metronidazole half-life and MRT were shorter in females than in males (p - 0.0014 and p = 0.0002, respectively). CONCLUSIONS: Data obtained in this study suggest that metronidazole clearance in females is about 12% higher than in males although these differences are probably of no clinical relevance.     

Uptake and disposition of inhaled methanol vapor in humans.

Methanol is a widely used solvent and a potential fuel for motor vehicles. Human kinetic data of methanol are sparse. As a basis for biological exposure monitoring and risk assessment, we studied the inhalation toxicokinetics of methanol vapor in four female and four male human volunteers during light physical exercise (50 W) in an exposure chamber. The relative uptake of methanol was about 50% (range 47-53%). Methanol in blood increased from a background level of about 20 to 116 and 244 microM after 2 h exposure at 0, 100 ppm (131 mg/m3) and 200 ppm (262 mg/m3), respectively. Saliva showed substantially higher levels than blood immediately after exposure. This difference disappeared in a few minutes; thereafter the concentrations and time courses in blood, urine, and saliva were similar, with half times of 1.4, 1.7, and 1.3 h, respectively. The postexposure decrease of methanol in exhaled air was faster, with a half time of 0.8 h. The methanol concentrations were approximately twice as high in all four types of biological samples at 200 compared to 100 ppm. No increase in urinary formic acid was seen in exposed subjects. Our study indicates non-saturated, dose-proportional kinetics of methanol up to 200 ppm for 2 h. No gender differences were detected. Similar, parallel patterns were seen with regard to the methanol time courses in blood, urine, and saliva, whereas the concentration in exhaled air decreased markedly faster. Thus, apart from blood and urine, saliva also seems suitable for biomonitoring of methanol exposure.     

Metabolism and disposition of simultaneously inhaled m-xylene and ethylbenzene in the rat

Rats were exposed for 5 days (6 hr/day) to one of four concentrations of a mixture of m-xylene (XYL) and ethylbenzene (EB) in the air (0 + 0, 75 + 25, 300 + 100, or 600 + 200 ppm). XYL and EB were found in the fat after the 5th day of exposure in the same molar ratio (3:1) as in the inspired air. The urine of the rats in each group was collected in two daily portions. The excretion of urinary thioethers increased linearly up to 12-fold. The urinary excretion of the major metabolites of XYL (methylhippuric acid, dimethylphenols, and methylbenzyl alcohol) and EB (hippuric, mandelic, phenylglyoxylic, and phenaceturic acids, and l-phenylethanol) were measured. XYL metabolites were excreted faster than EB metabolites in a manner pronounced with repetitive exposure and increasing dose. If the urinary elimination was expected to show the same molar ratio as in the inspired air (3:1), then total XYL metabolites were recovered in amounts lower than those of EB (about 2:1). The metabolite pattern of XYL showed no difference between mixed and pure equimolar exposures, whereas the pattern of EB metabolites was variable. The major problem met in quantitation of total output of EB was the estimation of metabolites (hippuric and phenaceturic acids) also formed endogenously. The apparent metabolic capacity for urinary solvent disposition vs the atmospheric concentration showed nonlinear correlation after a single mixed exposure. From the 2nd day onward, the metabolite excretion rates abruptly increased more than expected with the 600 + 200 ppm dose. This dose also increased microsomal drug-metabolizing activity in the liver. In conclusion, the mutual effects characteristic for mixed exposure to XYL + EB were, in a conspicuous manner, enhanced with the dose.     

Age related differences in the disposition of acetanilide.

1 The metabolism of fifteen elderly hospital in-patients and fifteen young people was studied, using a gas chromatography mass spectrometer method. 2 The results suggest that there is no significant change in hepatic oxidation of acetanilide with age. 3 The concentrations of metabolites were however, significantly elevated in the older group. 4 These results illustrate the importance of the decline in renal function with age in the disposition of drugs.     

Sex-related differences in drug disposition in man

Sex-related differences in the disposition of some analgesics, anxiolytics and hypnotics have recently been reported. With certain benzodiazepines, sex has been shown to be a more important determinant of variability in drug disposition than age, while with other benzodiazepines an age-related decline in clearance was more pronounced in men than women. In young healthy adults these sex-related differences in drug disposition were related to the phase of the menstrual cycle, oral contraceptive steroid administration, and variations in plasma concentrations of albumin, alpha 1-acid glycoprotein, free fatty acids and sex hormones. While none of the sex-related differences so far reported necessitates the modification of a therapeutic dosage regimen, it is prudent that future protocols for pharmacokinetic studies should regard age, sex, the menstrual cycle and oral contraceptive steroids as potential sources of variability.     

Ethnic differences in drug disposition and responsiveness

Interethnic differences are important factors accounting for interindividual variations in drug responsiveness. However, these differences in drug response have been a relatively neglected area of investigation, so that similar doses are prescribed to different ethnic populations without consideration of interethnic pharmacokinetic and pharmacodynamic variation. With the increased recognition of genetically determined polymorphism in metabolising ability as an important factor in drug disposition, concern has developed for the importance of individualising drug dose to account for racial differences. The recognition of these differences in drug disposition and responses calls into question the failure of drug licensing authorities to demand information on dosage, efficacy and toxicity in different ethnic groups, and to accept data from limited ethnic groups such as Caucasians. This article reviews the evidence for ethnic differences in drug disposition and sensitivity and should encourage further investigations to elucidate the extent of such differences, their causes and their therapeutic impact.     

The fate of isoprene inhaled by rats: comparison to butadiene

Isoprene (2-methyl-1,3-butadiene), a volatile monomer occurring in the natural environment and used in the manufacture of elastomers, is a close chemical relative of the animal carcinogen 1,3-butadiene. To obtain toxicokinetic data for inhaled isoprene, male F344 rats were exposed in groups of 30 to 14C-labeled isoprene vapor at four concentrations from 8 to 8200 ppm. The percentage of the inhaled isoprene that was metabolized decreased with increasing exposure concentration. The percentage of the total metabolites (that is, non-isoprene-retained 14C) excreted in urine and feces or expired was determined as a function of vapor concentration. About 75% of the total metabolites was excreted in urine. This was independent of inhaled isoprene concentration. After exposure to 8200 ppm, a larger percentage of the metabolites was excreted in feces than after exposure to lower concentrations. Using vacuum line techniques, blood metabolite concentrations were determined as functions of both vapor concentration and exposure duration. At one exposure concentration (1480 ppm) metabolites were measured in the nose, lungs, liver, kidney, and fat, as well as in blood. A mutagenic metabolite, isoprene diepoxide, was tentatively identified in all tissues examined. Between 0.0018 and 0.031% of the inhaled 14C label was tentatively identified as this metabolite in blood. The relative amount of the metabolites present in blood was highest for low concentrations of inhaled isoprene and for shorter exposure durations. Body fat appeared to be a reservoir for both isoprene metabolites and isoprene itself. The appearance of metabolites in the respiratory tract after short exposure durations together with low blood concentrations of isoprene indicated that substantial metabolism of inhaled isoprene in the respiratory tract may occur.     

Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV.

UK-427,857 (4, 4-difluoro-N-[(1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl]cyclohexanecarboxamide) is a novel CCR5 antagonist undergoing investigation for use in the treatment of human immunodeficiency virus (HIV) infection. Pharmacokinetic and metabolism studies have been performed in mouse, rat, dog, and human after single and multiple administration by oral and intravenous routes. The compound has physicochemical properties that are borderline for good pharmacokinetics, being moderately lipophilic (log D(7.4) 2.1) and basic (pK(a) 7.3), possessing a number of H-bonding functionalities, and with a molecular weight of 514. The compound was incompletely absorbed in rat (approximately 20-30%) but well absorbed in dog (>70%). Based on in vitro studies in Caco-2 cells, UK-427,857 has relatively poor membrane permeability, and transcellular flux is enhanced in the presence of inhibitors of P-glycoprotein. Further evidence for the involvement of P-glycoprotein in restricting the oral absorption of UK-427,857 was obtained in P-glycoprotein null mice (mdr1a/mdr1b knockout). In these animals, AUC after oral administration was 3-fold higher than in control animals. In oral dose escalation studies in humans, the compound demonstrated nonlinear pharmacokinetics, with increased dose-normalized exposure with increased dose size, consistent with saturation of P-glycoprotein. The oral dose-exposure relationship of UK-427,857 in humans was not reflected in either rat or dog. In animal species and humans, UK-427,857 undergoes some metabolism, with parent compound the major component present in the systemic circulation and excreta. Elimination of radioactive dose was primarily via the feces. In rat, parent compound was secreted via bile and directly into the gastrointestinal tract. Metabolites were products of oxidative metabolism and showed a high degree of structural consistency across species.     

Pulmonary disposition of inhaled NO2-nitrogen in isolated rat lungs

Nitrogen dioxide (NO2) is a relatively insoluble, reactive gas that, on inhalation, generates a diverse array of pulmonary toxic effects. Its uptake and transformation in isolated lungs have been shown to be proportional to inspired dose and associated with significant accumulations of the nitrite ion. However, not all absorbed NO2 is directly detectable as soluble nitrite. To further characterize its uptake and chemical disposition, we determined the chemical fate of 15NO2-nitrogen in isolated perfused (red cell-free) rat lungs that were exposed to 20 ppm 15NO2 for 60 min. Total excess 15N (relative to unexposed controls) was determined by isotope ratio mass spectrometry and total nitrogen analysis. Excess 15N was detected in whole lungs and in soluble and insoluble fractions but not in the total lipid pool. Perfusate excess 15N and nitrate correlated and accounted for all absorbed NO2 not detectable in tissue fractions. Exogenously instilled [15N]nitrite distributed within lung tissue, bound to insoluble elements, and diffused to the vascular space similar to NO2-nitrogen. Instilled [15N]nitrate did not distribute or bind like NO2-nitrogen or nitrite. Dialysis (1000 molecular weight cutoff) of cytosol, membranes, and perfusate removed excess 15N and nitrite derived from NO2, nitrite, or nitrate sources. We conclude that in isolated lungs, inhaled NO2 (1) undergoes rapid uptake and transformation in sites accessible to the pulmonary circulation; (2) does not form stable addition products with lipids; and (3) forms small-molecular-weight soluble reaction product(s) that behave similarly to nitrite, most likely indicating predominant univalent reduction of NO2 via initial hydrogen abstraction and subsequent HNO2 dissociation.     

Dosimetry and acute toxicity of inhaled butadiene diepoxide in rats and mice.

Butadiene diepoxide (BDO2), a metabolite of 1,3-butadiene (BD) and potent mutagen, is suspected to be a proximate carcinogen in the multisite tumorigenesis in B6C3F1 mice exposed to BD. Rats, in contrast to mice, do not form much BDO2 when exposed to BD, and they do not form cancers after exposure to the low levels of BD at which mice develop lung and heart tumors. Tests were planned to determine the direct carcinogenic potential of BDO2 in similarly exposed rats and mice, to see if they would develop tumors of the lung (the most sensitive target organ in BD-exposed mice) or other target tissues. The objective of the current series of studies was to assess the acute toxicity and dosimetry to blood and lung of BDO2 administered by various routes to B6C3F1 mice and Sprague-Dawley rats. The studies were needed to aid in the design of the carcinogenesis study. Initial studies using intraperitoneal injection of BDO2 were designed to determine the rate at which each of the species cleared the compound from the body; the clearance was equally fast in both species. A second study was designed to determine if the highly reactive BDO2, when deposited in the lung, would enter the bloodstream from the lung; intratracheally instilled BDO2 did enter the bloodstream, indicating that exposure via the lungs would result in BDO2 reaching other organs of the body. In a third study, rats and mice were exposed by inhalation for 6 h to 12 ppm BDO2 to determine blood and lung levels of the compound. Concentrations of BDO2 in the lung immediately after the exposure were 2 to 3 times higher than in the blood in both species (approximately 500 and 1000 pmol/g blood in the rat and mouse, respectively). As expected, mice received a higher dose/g tissue than did rats, consistent with the higher minute volume/kg body weight of the mice. The inhalation dosimetry study was followed by a histopathology study to determine the acute toxicity to rodents following a single, 6-h exposure to 18 ppm BDO2. No clinical signs of toxicity were observed; lesions were confined to the olfactory epithelium where areas of necrosis were observed. Analysis of bronchoalveolar lavage fluid did not indicate pulmonary inflammation. Based on these findings, an attempt was made to expose rats and mice repeatedly (for 7 days) to 10 and 20 ppm BDO2, but these exposure concentrations proved too toxic, due to inflammation of the nasal mucosa and occlusion of the nasal airway, a lesion that cannot be tolerated by obligate nose breathers. Finally, the toxicity of rats and mice exposed 6 h/day for 5 days to 0, 2.5, or 5.0 ppm BDO2 was determined. The repeated exposures caused no clinical signs of toxicity, nor were any lesions observed in the respiratory tract or other major organs. Therefore, the final design selected for the carcinogenesis study comprised exposing the rats and mice for 6 h/day, 5 days/week for 6 weeks to 0, 2.5, or 5.0 ppm BDO2.     

Species differences in zearalenone-reductase activity

Thin-layer and high-pressure liquid chromatography (HPLC) were used to investigate in several animal species the hepatic metabolites of zearalenone (ZEN), a non-steroidal oestrogenic fungal toxin produced by species of Fusarium. ZEN was reduced to zearalenol (ZEL) by the S-9 fraction of rat-liver homogenates in the presence of NADH or NADPH. In this species ZEN reductase showed two peaks of activity at pH 4.5 and 7.4. Of the species tested, cows showed the highest activity of NADH-dependent ZEN reductase in the hepatic S-9 fraction, followed in decreasing order by mice, pigs, rats, rabbits and guinea-pigs. The S-9 fraction of hamster liver showed optimal activity at pH 5.5 and 8.0 with NADH and at pH 6.0 and 8.5 with NADPH; NADPH was more efficient than NADH only in this species. HPLC showed that alpha-ZEL was a major hepatic metabolite in the rat, mouse, pig, cow and rabbit in incubations at pH 4.5 with either NADH or NADPH and at pH 7.4 with NADH, although at pH 7.4 with NADPH, beta-ZEL was the predominant metabolite. In guinea-pigs, both alpha- and beta-ZELs were produced in roughly similar amounts irrespective of the pH and cofactor, while in hamsters beta-ZEL was the major metabolite. These findings indicate that there are two types of ZEN reductase differing in optimum pH and that the stereospecific reduction of ZEN depends on the source of S-9 and cofactors. Since the oestrogenic activity of alpha-ZEL is about ten times greater than that of ZEN, the possible presence of ZEN metabolites in edible tissues of livestock fed on ZEN-contaminated feeds is an important mycotoxicological problem.