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Unless specifically exempted by the Health Protection Branch, New Drug Submissions for new drug products intended for sale in Canada should include comprehensive pharmacokinetic data on the drug ingredient(s) and their active metabolites, and appropriate evidence of bioavailability, or comparative bioavailability of the drug product. For generic products, acceptable evidence of bioequivalence is required as a condition of marketing. Although each drug is considered on its own merits, the evidence for a conventional dose-form is usually deemed to be acceptable if: (1) comparative studies of the test versus reference product, based on concentrations of the active drug and/or its metabolites, indicate that the shortest 95% confidence interval for relative mean area under the drug concentration time curve (AUC) is between 80 and 125% and (2) the relative mean Cmax is between 80 and 125%.For certain drugs, such as those for acute use and controlled-release formulations, the conditions of testing and acceptable...

The stability of adrenochrome solutions in the presence of several inorganic compounds has been studied.The purity and stability of several "aged" and commercial samples of adrenochrome have been evaluated.The stability of solutions of adrenochrome in some of the lower aliphatic alcohols has been examined.

The rates of rearrangement of several aminochromes have been measured in: (1) water, (2) aqueous sodium hydroxide, and (3) aqueous zinc acetate. The rates were found to be first order with respect to aminochrome concentration in each reaction medium, and to zinc acetate concentration. However, no simple kinetic relationship between the rate of rearrangement and alkali concentration was detected. The rate increased very rapidly with increasing alkali concentration.Mechanisms for these rearrangements are suggested, based on the influence of substituents in the 1-, 2-, and 3-positions of the aminochrome molecule on the kinetic and thermodynamic features of the reaction.

The iodination of adrenochrome by iodine is subject to general base catalysis. This is in accord with the view that the rate-determining step in this reaction is the removal of the C-7 proton in the adrenochrome. The order of catalytic activities of the various ions is phosphate > bicarbonate > propionate > acetate, which is also the sequence of the pKa values of the corresponding acids. However, the catalytic efficiencies of the hydrogen phthalate and phthalate anions are about 10 times greater than those predicted from the dissociation constants of the acid. This is rationalized in terms of an alternative electrophilic–nucleophilic catalysis of the iodination reaction.

The kinetics of the iodination of several aminochromes by iodine in aqueous potassium iodide, to form the 7-iodo derivatives, have been studied. The rate of iodination is directly dependent on the concentrations of the aminochrome and iodine and varies inversely with the first power of the iodide ion concentration. The rate of reaction is independent of pH, but the reaction is subject to general base catalysis. A mechanism for the iodination of aminochromes is proposed. The reactive species are molecular iodine and the zwitterionic form of adrenochrome, and the reaction proceeds via a quinonoid intermediate. The rate-controlling process is the removal of the C-7 proton.

7-Iodoadrenochrome reacts with glutathione to give 5,6-dihydroxy-7-iodo-1-methylindole, 5,6-dihydroxy-1-methylindole, 7-S-glutathionyl-5,6-dihydroxy-1-methylindole, and a trace of a product that is probably 4-S-glutathionyl-5,6-dihydroxy-7-iodo-1-methylindole. It reacts with the monosodium salt of glutathione to give mainly 5,6-dihydroxy-7-iodo-1-methylindole and 4-S-glutathionyl-5,6-dihydroxy-7-iodo-1-methylindole, with smaller quantities of 7-S-glutathionyl-5,6-dihydroxy-1-methylindole and 5,6-dihydroxy-1-methylindole. 7-Bromoadrenochrome reacts with glutathione (free acid or monosodium salt) to give mainly 7-bromo-5,6-dihydroxy-1-methylindole and a second product, which is probably 7-bromo-4-S-glutathionyl-5,6-dihydroxy-1-methylindole. The main products that are obtained in reactions of this type result from either direct reduction of the aminochrome or 1,4-addition of the thiol to either of the α,β-unsaturated C5-carbonyl systems in the aminochrome molecule.

Blood concentration and urinary excretion data demonstrated that subjects who had ingested 1 g of paracetamol after fasting overnight absorbed the drug up to 5 times more rapidly but to the same extent as when they ingested the drug after a substantial high carbohydrate breakfast. Subjects who had ingested 1 g of paracetamol immediately before sleep at night excreted up to 36% less than when they took the drug at 8.30 a.m.

The nitromethane-Hyamine method for assay of nitrofurantoin in whole blood has been improved: smaller volumes of blood (0.8 ml) are required, the sensitivity is greater (0.2 pg/mI), and the solution to be read is more stable than in the original method. The analysis detects 70 to 72% of 1 to 4 Ag of nitrofurantoin added per milliliter of whole blood. Blood concen-trations after the usual therapeutic peroral dose (100 mg) of nitrofurantoin are reported.

The reactions between aminochromes and thiols have been reinvestigated. In general aminochromes react with thiols to give mixtures of products including: 5,6-dihydroxyindoles; thio-substituted 5,6-dihydroxyindoles (the mercapto residue is now considered to be in the 4-position of the indole nucleus and not the 7-position as previously reported); and relatively unstable addition products formed between the aminochrome and the thiol. The mechanisms by which these compounds are formed are discussed. The characterization of three thio-substituted 5,6-dihydroxyindoles by nuclear magnetic resonance spectroscopy is described. The nuclear magnetic resonance spectra of a number of 5,6-diacetoxyindole derivatives are reported.

The reaction between adrenochrome and glutathione has been studied. The main products result from the 1,4-addition of glutathione to the C5 unsaturated carbonyl systems in adrenochrome involving the C6—C7 and the C4—C9 double bonds, and are probably 7-S-glutathionyl-5,6-dihydroxy-N-methylindole and 9-S-glutathionyl-2,3,6,9-tetrahydro-3,5-dihydroxy-6-oxo-N-methylindole respectively. 5,6-Dihydroxy-N-methylindole is also formed during the interaction of glutathione and adrenochrome. The mechanisms by which these compounds are formed are discussed.

A method is described for the determination of the individual levels of adrenaline, noradrenaline, dopamine, metanephrine and normetanephrine in urine. The amines present in the urine are adsorbed on a weak cation exchange resin (Amberlite IRC-50) and the catecholamines then eluted by a boric acid solution followed by metanephrine and normetanephrine with dilute sulfuric acid. The amines in each fraction are oxidised by iodine to the corresponding aminochromes which are then converted to their sodium bisulfite addition compounds. The levels of each of the five amines are calculated from measurements of the absorbances, at several wave-lengths, of the solutions of the bisulfite addition compounds. The average excretion rates of the free amines in urine, based on 41 determinations using this method are (in μg/h): A∗∗∗, 0.04; N.2.36; D.8.22; M, 1.25; NM, 8.55. The corresponding excretion rates (in μg/h) for the total amines (i.e. free plus conjugated) are: A, 0.06; N, 4.69; D, 27.20; M, 3.65; N.M. 17.48.

A method is described for the separation and estimation of 4-, 5-, 6-, and 7-hydroxyskatole sulfate esters in urine. After extraction from urine, the 5-, 6-, and 7-hydroxyskatole sulfate esters were hydrolyzed by a sulfatase preparation to the corresponding hydroxyskatoles. The 4-isomer was resistant to this enzymic hydrolysis. The hydroxyskatoles were then extracted by ethyl acetate from the hydrolyzate followed by extraction of the 4-sulfate ester by n-butanol. Each fraction was chromatographed on silica gel G thin layers, sprayed with a modified Ehrlich's reagent (p-N,N-bis(2-chloroethyl)aminobenzaldehyde), and the appropriate zones eluted from the chromatogram. The concentrations of each isomer originally present in the urine were estimated from the absorbances of the four eluates at their absorption maxima (ca. 600 mμ). The levels of the four isomeric skatolyl sulfates found in urines from 10 normal controls are given.

THE discharge of the intense red colour of aqueous solutions of adrenochrome (I) by various reducing agents has been reported by several workers1,2. The reaction apparently does not simply consist of the reduction of the orthoquinone moiety of the molecule with the production of the hypothetical ‘leuco-adrenochrome’ (2 : 3-dihydro-3 : 5 : 6-trihydroxy-N-methylindole) (II). Harley-Mason, in describing the reduction with sodium hydrosulphite or hydrogen (catalytic), postulated the initial addition of one atom of hydrogen to the molecule, with the formation of an unstable intermediate which disproportionates into (II) and a zwitterionic compound (III). The former (II) appears to be inherently unstable and readily loses water, with the formation of 5 : 6-di-hydroxy-N-methylindole (IV) ; the second substance (III) isomerizes under the influence of alkali to adrenolutin (3 : 5 : 6-trihydroxy-N-methylindole) (V)2,3.

Significant differences have been found between the concentrations of free dopamine excreted in the urine of normal individuals and schizophrenic patients.

ACKNOWLEDGMENTS Acad. Sci., Sect. A, 56,71 (1962). 3. N. S. BHACCA, D. P. HOLLIS, L. F. JOHNSON, We are deeply indebted to Dr. G. E. A. PIER. and 1. N. SHOOLERY. NMR s~ectra Snatzke and his colleagues (Bonn Univercatalog. ~ b l . 1." Varian Associates, palo' Alto, California. 1962. sity) for making the magnetic 4. J. A. ELVIDGE and R. G. FOSTER. J. Chem. Soc. resonance spectral measurements, and to 590 (1963). Professor K. Schreiber (Gatersleben, East 5. giE. ~ ~ ~ ~ ~ l ~ & ! ~ . L . WoRDeN. J. 0% Germany) for helpful discussions. 6. E. A. ABU-MUSTAFA and M. B. E. FAYEZ. 1. Org.. Chem. 26.161 11961). 7. g. b?. DEAN. ~orts'chr. 'chem. Org. NaturI. YE. N. SHEINKER, G. Yu. PEK, and M. E. stoffe, 9,225 (1952). PERELSON. Dokl. Akad. Nauk SSSR, 158,1382 8. M. E. BROKKE and B. E. CHRISTENSEN. (1964). 1. Ora. Chem. 23,589 (1958). . . 2. T. J: BATTERHAM and J. A. LAMBERTON. Australian J. Chem. 17, 1305 (1964). S. S. RECEIVED JUNE^, 1966. DHARMATTI, G. GOVI, C. R. KANEKAR, C. L. NATIONAL RESEARCH CENTRE, KHETRAPOL, and U. P. VIRMANI. Proc. Indian DOKKI, CAIRO, UNITED ARAB REPUBLIC.

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