The disposition of tiludronate in mouse, rat, rabbit, dog and monkey has been studied after oral and intravenous doses. Like other bisphosphonates, tiludronate was characterized by poor absorption from the gastrointestinal tract. Peak plasma concentrations appeared shortly (0.5-1 h) after dosing, except for the baboon (4.5 h). Food intake highly impaired intestinal absorption The affinity of tiludronate for bone and the slow release from this deep compartment could account for the large volume of distribution and the low plasma clearance found in all species. Tiludronate has low affinity for red blood cells and binds moderately to serum proteins, mainly to serum albumin. Calcified tissues appeared to be the main target for deposition. Distribution into bone was not homogenous, with higher levels in the trabecular bone than in the corticol part of the long bones. The uptake of tiludronate into bone was unequivocally less in the older animal. No metabolism occurred in the tested animal species. The major route of elimination of the absorbed drug is urine. Preclinical observations made with tiludronate, like with other bisphosphonates, were predictive of results obtained in clinical investigation.

1. [14C]Minaprine was administered as a single oral dose to five animal species and to a healthy and informed volunteer. Excretion of radioactivity was followed during 48 h in urine and faces; biliary excretion was followed only in rat. 2. Urinary metabolites were isolated and identified by mass spectrometry. 3. A quantitative comparison of metabolites in different species was made. On the basis of these data it it concluded that the dog is not a suitable model for man for pharmacological or toxicological studies. 4. The major metabolic route is 4-hydroxylation of the aromatic ring. The only unexpected metabolic route found was the biotransformation of the morpholino ring, probably by reductive ring-cleavage. 5. About 50% of the 14C was excreted in 0-48 h urine. The other 50% was excreted in the 0-48 h faces. In the rat, this was attribute entirely to biliary excretion. The drug is well absorbed after oral administration and is not accumulated in the body.

1. The metabolism of minaprine and its major metabolite p-hydroxyminaprine were studied using hepatocytes and liver microsomes from different species. Metabolism of this drug in vitro was then compared with in vivo data already published. 2. Our results showed that the major metabolic route (4-hydroxylation of the aromatic ring) is the same in the two experimental systems. Other in vivo biotransformation pathways (i.e. N-oxidation, reductive ring cleavage, N-dealkylation, oxidation) were also confirmed in hepatocytes. 3. Similar inter-species variability was observed both in vitro and in vivo. The present study has led to the same conclusion as previous in vivo metabolic investigations, namely, that metabolism in the dog quantitatively differs from that observed in other animal species. 4. These results clearly demonstrate that in vitro models (i.e. isolated hepatocytes and liver microsomes) are powerful tools in predicting the metabolic pathways of a drug in man and animal species.

[14C]-Penticainide, 2-[2-(diisopropylamino) ethyl]-4-methyl-2-(2-pyridyl)pentanamide, a new antiarrhythmic agent, was administered as a single oral dose to rats, dogs, baboons (30 mg kg-1) and to healthy, informed volunteers (300 mg). Excretion of radioactivity was followed for 3 days in urine and faeces. In man, about 95% of the administered radioactivity was eliminated in the urine and levels ranging from 56 to 86% were observed in animals. The radioactivity that did not appear in the urine was almost quantitatively recovered in the faeces. Metabolites in urine were isolated by thin-layer chromatography and identified by mass spectrometry and nuclear magnetic resonance. In addition to the unchanged drug, nine metabolites and an artifact compound resulting from the partial degradation of one metabolite, were identified among the thirteen radioactive compounds detected. The major metabolites resulted from N-dealkylation of the diisopropyl moiety, oxidation of the isobutyl side-chain and hydrolytic cleavage of the amide. Comparison of the excretion and metabolic patterns of animals with those of man revealed that the dog should be a most suitable model for predicting the pharmacological and toxicological effects of penticainide in man.

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