No abstract

The rapid development of stereospecific analytical, synthetic, and preparative methods has profoundly changed the prospects for development and application of chiral medicinal products. This has induced regulatory agencies, e.g., in Canada, the EEC, Japan, and the United States, to prepare guidance on this subject. The present draft documents are discussed, with emphasis on the two most important cases: (1) New racemates: How many extra requirements are justified? (2) Development of a single enantiomer from an approved racemate: how few are acceptable? At the moment the opportunities for early harmonisation are favourable and the formulation of one international guidance document seems feasible.

Amygdalin (D-mandelonitrile-beta-D-gentiobioside) is a cyanogenic glycoside claimed to show anti-cancer activity, sold under the incorrect name "Laetrile". For a sensible discussion of its alleged activity and its established toxicity it is necessary that its fate in the organism is known. The pharmacokinetics of amygdalin have been investigated in the Beagle dog after both intravenous and oral administration. The excretion of amygdalin has also been studied in the rat. Amygdalin concentrations were determined by high performance liquid chromatography in plasma ultrafiltrate and urine. The pharmacokinetics of amygdalin after intravenous administration were compared with those of diatrizoate, a model substance for extracellular volume and glomerular filtration. The amygdalin clearance is significantly larger than that of diatrizoate. The volumes of distribution of both substance are the same. After oral administration only a few percents of the amygdalin dose are systemically available. A part of the oral dose is recovered from the urine as prunasin (D-mandelonitrile-beta-D-glucoside).

1 The small-intestinal transfer of prunasin (D-mandelo nitrile-β-D-glucoside), the primary metabolite of amyg dalin which is not absorbed in the small intestine as such, was studied in rat jejunum and ileum in vitro. 2 As shown by high pressure liquid chromatography, prunasin is transferred essentially intact across the intesti nal wall, without cleavage of the glycosidic bond and thus no formation of benzaldehyde or cyanide during the mucosal passage. 3 Only the jejunal transfer of prunasin followed satura tion kinetics (vmax = 1.6 μmol cm-1 min-1; KT = 460 μmol l-1) and exhibited a clearsodium-ion dependence. As indicated by the temperature dependence, only the jejunal mucosa- to-serosa transfer and the corresponding tissue uptake of prunasin required apparently high activation energies. Transfer in the terminal ileum showed diffusion character istics. 4 Jejunal methyl α-D-glucoside transfer was inhibited by the presence of prunasin. Furthermore, the tissue uptake of methyl α-D-glucoside in rat jejunum was competitively inhibited by prunasin. 5 The results indicate that prunasin is absorbed unmetabolised in the jejunum of the rat via the transport system of glucose.

The pharmacokinetics of prunasin have been investigated in the dog. The results are compared with results obtained with amygdalin. The volume of distribution and the clearance of prunasin are larger than those of amygdalin. The oral bioavailability of prunasin is approximately 50%, whereas amygdalin is hardly absorbed unchanged.