Purpose: Nemorubicin (3V-deamino-3V-[2 00 (S)-methoxy-4 00 -morpholinyl]doxorubicin; MMDX) is an investigational drug currently in phase II/III clinical testing in hepatocellular carcinoma. A bioactivation product of MMDX, 3V-deamino-3 00 ,4V-anhydro-[2 00 (S)-methoxy-3 00 (R)-oxy-4 00 -morpholinyl]doxorubicin (PNU-159682), has been recently identified in an incubate of the drug with NADPHsupplemented rat liver microsomes. The aims of this study were to obtain information about MMDX biotransformation to PNU-159682 in humans, and to explore the antitumor activity of PNU-159682.Experimental Design: Human liver microsomes (HLM) and microsomes from genetically engineered cell lines expressing individual human cytochrome P450s (CYP) were used to study MMDX biotransformation. We also examined the cytotoxicity and antitumor activity of PNU-159682 using a panel of in vitro-cultured human tumor cell lines and tumor-bearing mice, respectively.Results: HLMs converted MMDX to a major metabolite, whose retention time in liquid chromatography and ion fragmentation in tandem mass spectrometry were identical to those of synthetic PNU-159682. In a bank of HLMs from 10 donors, rates of PNU-159682 formation correlated significantly with three distinct CYP3A-mediated activities. Troleandomycin and ketoconazole, both inhibitors of CYP3A, markedly reduced PNU-159682 formation by HLMs; the reaction was also concentration-dependently inhibited by a monoclonal antibody to CYP3A4/5. Of the 10 cDNA-expressed CYPs examined, only CYP3A4 formed PNU-159682. In addition, PNU-159682 was remarkably more cytotoxic than MMDX and doxorubicin in vitro, and was effective in the two in vivo tumor models tested, i.e., disseminated murine L1210 leukemia and MX-1 human mammary carcinoma xenografts.Conclusions: CYP3A4, the major CYP in human liver, converts MMDX to a more cytotoxic metabolite, PNU-159682, which retains antitumor activity in vivo.
14C-Rifabutin was given orally to rats, rabbits and monkeys at a dose of 25 mg/kg and to healthy volunteers at a dose of 270 mg. Radioactivity was eliminated by both the renal and faecal routes in all species, with a predominance of the renal route in man and monkeys (50.19% and 46.73% of the dose, respectively, in urine at 96 h), whereas in rats and rabbits a slight predominance of faecal excretion was observed (48.09% and 45.01% of the dose, respectively, at 96 h in faeces; 42.22% and 36.37% in urine). Radioactivity as expired 14CO2 was detected in the rat and accounted for less than 0.5% of the dose within 96 h. The drug was rapidly absorbed and peak plasma radioactivity levels were reached from 1 to 4 h after dosing. Rifabutin was the predominant compound circulating in plasma at the first sampling times, but significant levels of 31-OH rifabutin were detected up to 8-24 h in all species studied. 25-O-deacetyl rifabutin was detected only in rat and man. Polar metabolites were also present, particularly at the later sampling times. The urinary metabolism was studied by radio-HPLC. Rifabutin accounted for 8.5% and 4.6% of the dose in 0-24 h urine of rats and man respectively, whereas in rabbit and monkey urine only traces of this compound were detected. The main known metabolite in all animal species was 31-OH rifabutin; 25-O-deacetyl rifabutin was detected only in rat and man. The remaining urinary radioactivity was mainly due to polar compounds.
The purpose of this study was to compare the disposition and the metabolic pattern of Reboxetine in several species, including man. e 4 C]-Reboxetine was given orally to the rat, the dog, the monkey (5 mglkg) and man (2 and 4 mglkg). Radioactivity was eliminated both by the renal and faecal route in the rat and the dog, mainly in urine in the monkey and man. Reboxetine was extensively metabolized. A number of urinary metabolites were quantified by radio-HPLC and tentatively identified by comparison with the retention times of reference compounds.Suggested routes of metabolic transformation are: 2-0-dealkylation; hydroxylation of the ethoxyphenoxy ring; oxidation of the morpholine ring; morpholine ring-opening; and combinations of these. Metabolites were partially or completely conjugated with glucuronic acid and/or sulphuric acid.
GIORGIO MELLERIO', GIOI-ASSI T-IDARI* and P.io~.i I-ITA-FISSI~ * ?Isfituto di Chiniica Organicci--ni;,ersita degli Studi-lCale W r a n i e l l i 10-27100 PaLmia (Italy) 3Centro del C-TR p e r lo Studio delle Sostanre Organiche .\htiirali-Politecnico-Piarra L e o m r d o do Ti'nci 32-20133 X i l a n o (Italjj ;iBsTR.icT.-From lots of Lncfarrzts scrobzciilnfus extracted in different B-ays, in addition to ethyl linoleate and cerevisterol, nine lactarane sesquiterpenes have been isolated. The main compounds are furanosesquiterpenes, namely: furoscrobiculins -4-D (2, S-i), furanethers 13 and 4) and the already known lactaral (l), and furandiol 19a). Furthermore a new sesquiterpene lactone with the CO group in 13, lactaroscrobiculide B (8), has been isolated. The structures were elucidated mainly by spectroscopic methods and by some chemical transformations. Stereochemistry of most sesquiterpenes has been determined.Recently (1-3) we isolated from Lactariids scrobiciilatzks some sesquiterpenes 11-ith the lactarane skeleton which is peculiar to most of the knon-n Russulaceae metabolites (4-1i). At present the only mushrooms of this family containing sesquiterpenes with a completely different skeleton are L. deliciosus (1s) (guaianes) and L. uzidzis (19) (drimanes).Sou-11-e report the structures of ne!\ lactarane sesquiterpenes which were isolated from a nen-lot of L. scrobiciilatus extracted in a different way than in the previous \I ork (2. 3). DISCCSSIOSL. scrobiczilatus is easily distinguished not only by the morphological aspects (yellow color, big size. wrobiculated stem, pungent taste, etc.), but also by the secreted milky juice, n-hich, for some reason not yet understood, turns quickly from n hite to yelloJv when it appears at the surface of the fruit-body. This color change could indicate enzymatic degradation reactions : therefore, in order to prevent and to check possible alterations in the sesquiterpene composition. n-e carried out extraction in three different nays:The frozen material \vas then minced under its solvent and. after being removed by filtration. it was homogenized in ethanol and ice to extract the more polar compounds.b) The freshly collected mushrooms nere cut and put in acetone. The material \vas norked up in a dry-box under a S? stream as in a). In this case, the color change in the juice seemed to be slon-er but n-as still noticeable.a) The fruit-bodies nere frozen in drj ice and acetone.c) The fruit-bodiei n ere cut without any precaution.
The pharmacokinetics of FCE 22101 were studied in rats, rabbits, Cynomolgus monkeys and dogs after intravenous administration. Pertinent pharmacokinetic parameters were determined according to a two-compartment model and correlated among species as an exponential function of body weight, thereby allowing an estimation of pharmacokinetic parameters corresponding to a 70 kg man. Allometric equations, including data on humans reported in the literature, were also established and used to study similarities and differences in the disposition of FCE 22101 among species. The pharmacokinetic profile of FCE 22101 was consistent with the principles of allometry in all animal species studied (and in man) with the exception of the Cynomolgus monkey, in which clearance of FCE 22101 was slower than expected.
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