Human moricizine metabolism. II. Quantification and pharmacokinetics of plasma and urinary metabolites.

1. The metabolism of moricizine.HCl was studied in 12 male volunteers dosed with 250 mg (300 microCi) 14C-radiolabelled drug. 2. Moricizine was biotransformed to many metabolites in humans (at least 35 plasma and 51 urine metabolites). 3. Urine and faecal combined mean (range) recovery accounted for 90.2% (73.4-101.6%) of the administered radioactivity, with most of the recovered radioactivity present in faeces (mean 58.4%; range 45.6-64.7%). Mean (range) urinary recovery was 31.8% (26.2-36.9%), with <1% of the dose recovered as intact moricizine, and no one metabolite accounting for >2.5% of the dose. 4. Total radioactivity (TR) plasma t1/2 was 85.2 h, while that for moricizine was 2.4 h. Mean half-lives for plasma metabolites ranged from 2.9 to 23.6 h. The largest portion (11%) of TR AUC (area under the plasma concentration-time curve) was attributed to 2amino-10-glucuronophenothiazine. Each of the other metabolites accounted for less of the TR AUC than parent drug except for two unidentified peaks which had comparable areas (approximately 5% of the total radioactivity area). 5. Two identified moricizine metabolites, 2-amino-10-(3-morpholinopropionyl) phenothiazine and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate, possess the structural characteristics proposed for class 1 anti-arrhythmic activity (pendant amine functionality) and have plasma half-lives 4-7-fold longer than moricizine.

Biological evaluation of radiolabeled D-methionine as a parent compound in potential nuclear imaging.

Based on the high radioactivity uptake of some 14C-labeled D-amino acids in tumors and pancreas of mice, this investigation was undertaken to ascertain possible usefulness of radioactive D-methionine as a nuclear imaging agent. Radioactivity derived from D-[3,4-14C]-methionine in Ehrlich solid tumor was approximately three times higher than that from the L-isomer, but was the same as for mouse pancreas. Excretion rate of the radioactivity of D-[14C]-methionine into urine was approximately two times faster than that of the L-isomer. As compared with two potential imaging agents, 1-aminocyclopentane-1-carboxylic acid and alpha-aminoisobutyric acid, D-methionine showed almost the same radioactivity biodistribution in tumor and pancreas. These results suggest potential for D-methionine as a mother compound for use in tumor and pancreas imaging.

Stimulating effects of inosine, uridine and glutamine on the tissue distribution of radioactive D-leucine in tumor bearing mice.

This experiment was carried out in search for stimulators of the in vivo uptake of D- and L-leucine by tumor and pancreas for the possible application to gamma-emitter labeled amino acids in nuclear medical diagnosis. Inosine, uridine, and glutamine which are stimulators of the in vitro incorporation of radioactive L-amino acids into some tumor cells significantly enhanced the uptake of D-leucine into the pancreas, while in Ehrlich solid tumor only a little if any increase was observed. Of the compounds tested inosine showed the highest stimulation of pancreas uptake in the range of doses used, resulting in the best pancreas-to-liver concentration ratio, a factor of significant consideration for pancreas imaging. The uptake of L-leucine by the tumor and pancreas was little affected by these compounds.

Tumor selective enhancement of radioactivity uptake in mice treated with alpha-difluoromethylornithine prior to administration of 14C-putrescine.

A group of EMT6 tumor bearing male BALB/c mice which had been treated with alpha-difluoromethylornithine (DFMO, a specific, irreversible inhibitor of ornithine decarboxylase, the enzyme which catalyzes the biosynthesis of putrescine), 8 mg/mouse, ip, 20 and 5 hrs before the 14C-putrescine dose, and a group of control animals were administered 14C-putrescine (0.5 muCi, 0.1 mCi/mmol, iv) 60 min prior to sacrifice. Radioactivity uptake data was obtained for the tumor and 13 major normal organs. In the control animals the tumor exhibited one of the highest uptakes of radioactivity. For DFMO-pretreated mice the radioactivity distribution among most of the normal tissues was not very different from that obtained for the control animals. However, the uptake into the tumor was enhanced by a factor of approximately 4. So, high tumor-to-tissue ratios (3.8, lung to 38, brain) were attained as a result of DFMO treatment.