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The novel taxanes SB-T-1102, SB-T-1214 and SB-T-1216 are up to 1000-fold more cytotoxic for resistant tumour cells than clinically used paclitaxel and docetaxel, and the current study has examined the metabolism of these new taxanes in human, rat, pig and minipig liver microsomes. Metabolites were characterized by high-performance liquid chromatography (HPLC)/tandem mass spectrometry (MS/MS) analysis. Metabolic pathways derived from their structures were confirmed by investigating subsequent metabolism of purified metabolites. SB-T-1102, SB-T-1214 and SB-T-1216 were metabolized to 14, 10 and 11 products, respectively. In contrast to docetaxel, side-chain hydroxylation did not occur at their tert-butyl group, but on the isobutyl (SB-T-1102) or isobutenyl (SB-T-1214 and SB-T-1216) chains. Species differences in their metabolism were observed. For example, human and untreated rat microsomes hydroxylated SB-T-1216 preferentially at the side-chain, whereas pig and minipig microsomes preferentially metabolized more at the taxane core. The increased formation of secondary and tertiary metabolites in rat microsomes with high expression of CYP3A1/2 compared with uninduced rats confirmed the role of CYP3A in taxane metabolism. All major products were formed by human cDNA-expressed CYP3A4 and none by CYP1A2, 1B1, 2A6, 2C9 and 2E1, indicating the principal role of CYP3A orthologues in SB-T metabolism. The knowledge of metabolic pathways of the examined agents and of their rates of formation is important due to possible metabolic inactivation of these three novel drugs with a great potential for the therapy of taxane-resistant tumours. The relatively slow metabolism of SB-T-1102 could be favourable for its antitumour efficiency in vivo.

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The aim of this study was to evaluate the efficiency of metabolism of acrylonitrile (ACN) to N-acetyl-S-(2-cyanoethyl)-L-cysteine (2-cyanoethylmercapturic acid (CEMA) in man, the kinetics of excretion of this metabolite, and the relation between the uptake of ACN and the excretion of CEMA in urine. Eleven experiments were performed on six male volunteers exposed for eight hours to ACN at concentrations of 5 or 10 mg/m3. The average respiratory retention of ACN was 52% and 21 8% of the retained ACN was excreted as CEMA in urine. Elimination approximated first order kinetics with half life of about eight hours. The best correlation between the uptake of ACN in the lungs and excretion of CEMA in urine was obtained when the concentration of CEMA in the urine fraction, collected between the sixth and eighth hours after the beginning of exposure, was adjusted to a specific gravity of 1-016 (y = 0 33x -13-3; r = 0 83). CEMA excretion, however, cannot be used as an individual index of exposure.According to the International Agency for Research on Cancer there is sufficient evidence for the carcinogenicity of Acrylonitrile (ACN) in animals.1 Though there is only limited evidence for the carcinogenicity of ACN in man it seemed worth while to investigate the absorption of ACN by all routes.Acrylonitrile may be absorbed through the respiratory tract (the retention of vapour is 46%) and liquid ACN is absorbed through the skin at the rate of 0-6mg/cm2/h.2 At present, no reliable method for evaluating internal exposure to ACN is available. Accepted 31 October 1986 showed that CEMA is the main metabolite of ACN and that in rats about 50-60% of the dose is excreted in urine in this form. Therefore, excretion of CEMA seems to have the potential to be an index of internal exposure to ACN.In preliminary studies Dramifnski and Trojanowska confirmed the presence of CEMA in the urine of workers engaged in manufacturing acryl fibres (unpublished data). The concentration of CEMA in urine collected at the end of the shift varied between 25 and 350 mg/l. The sensitivity of the method, however, did not allow for the evaluation of the kinetics of CEMA excretion in urine.The present study aimed to determine the efficiency of ACN metabolism to CEMA, the kinetics of urinary CEMA excretion, and to find a correlation between CEMA excretion in the urine and the absorbed dose of ACN.

Amphetamine-based drugs, including methamphetamine, are some of the most widely used illegal drugs in the world. Methamphetamine is metabolized by the cytochrome P450s, the latter also being involved in the metabolism of many drugs and other xenobiotics. The effect of methamphetamine pretreatment (10 mg kg-1, intraperitoneally once daily for 6 days) on the activity of the P450 enzymes was assessed both in the rat isolated perfused liver and in vivo. The rate of 4-hydroxydiclofenac production was significantly enhanced in vivo, indicating a possible stimulatory effect on P4502C6. Similarly, the kinetics of tolbutamide and dextromethorphan in isolated perfused rat liver indicate a significant increase in both P4502C6 and the P4502D subfamily. No significant changes in midazolam kinetic in the isolated perfused rat liver were observed. The potential for methamphetamine to cause drug interactions is of clinical relevance and, therefore, it warrants further investigation. Until further drug interaction experiments are accomplished, the co-administration of drugs with methamphetamine should be conducted with caution.

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Biotransformation of styrene and its toxic metabolite, phenyloxirane (1), in mice in vivo was studied. Mice were treated with single intraperitoneal doses of styrene (400 mg/kg of body weight), and with (R)-, (S)-, or racemic styrene oxide (150 mg/kg of body weight). Profiles of neutral and acidic metabolites were determined by GC/MS. Mandelic acid (3) and two mercapturic acids, N-acetyl-S-(2-hydroxy-2-phenylethyl)cysteine (5) and N-acetyl-S-(2-hydroxy-1-phenylethyl)cysteine (6), were found to be major urinary metabolites of both styrene and phenyloxirane. 1-Phenylethane-1,2-diol (2) was the main neutral metabolite. The rate of excretion of this metabolite, as determined by GC, was 5-10 times lower than that of mandelic acid. Several minor acidic metabolites were also identified. Among them, novel phenolic metabolites, namely, 2-(4-hydroxyphenyl)ethanol (7), (4-hydroxyphenyl)acetic acid (11), and two isomeric hydroxymandelic acids (12), are of toxicological significance. Main stereogenic metabolites were isolated as methyl esters from extracts of pooled acidified urine treated with diazomethane. The mandelic acid that was obtained was converted to diastereomeric Mosher's derivatives prior to analysis by NMR. Mercapturic acids were analyzed directly by (13)C NMR. Pure enantiomers of 1 were metabolized predominantly but not exclusively to corresponding enantiomers of 3. Styrene yielded predominantly (S)-mandelic acid. Fractions of mercapturic acids 5 and 6 isolated from urine amounted to 12-15% of the dose for all compounds that were administered. Conversion to mercapturic acids was highly regio- and stereoselective, yielding predominantly regioisomer 5. Styrene, as compared to racemic phenyloxirane, yielded slightly more diastereomers arising from (S)-1 than from (R)-1. These data can be explained by formation of a moderate excess of the less mutagenic (S)-1 in the metabolic activation of styrene in mice in vivo.