Lack of mutagenicity of nifedipine: a possible metabolic implication.

Nifedipine, being a nitro aromatic compound, is capable of undergoing reduction via hydroxyl-amino intermediate to an amine. Such an intermediate is a mutagenic culprit. The urinary metabolites of nifedipine were investigated in order to allay the fear of the existence of this metabolic route in humans. Nifedipine (20 mg) was administered twice daily for 2 weeks. No nitro-reduction product was detected over a 1-month period. Nifedipine lacks mutagenicity in the absence or presence of drug metabolizing microsomes in Salmonella typhimurium TA 98 and Salmonella typhimurium TA 100.

The anticoagulant activity of some selected warfarin analogues.

The anticoagulant activities of 6-, 7-, 8-, 4'-hydroxy, 6-chloro- and 6-bromowarfarin were determined in rabbits after intraperitoneal administration of 16.2 mumol kg-1 over 96 h. Substitution on the 4-hydroxycoumarin moiety resulted in reduction of the anticoagulant activity. 6-Chlorowarfarin was more potent than 6-bromowarfarin suggesting that the molecular size of 4-hydroxycoumarin moiety may be crucial for biological activity.

Chemical and statistical considerations in the determination of partition coefficients of weakly ionizable drugs and poisons.

Equations have been developed that relate the concentration (or a parameter directly proportional to concentration, such as optical absorbance) of a weakly ionizable solute in a water-immiscible phase, in equilibrium with an aqueous phase, to the pH of the aqueous phase, the partition coefficient of the unionized solute and the phase volume ratio. These relationships have been used in the design of experimental methods for determining partition coefficients, which require measurement of solute concentration in only one phase. Data obtained in this way permit ready recognition of deviations from assumptions made in the development of the model; these assumptions include insolubility of the ionized solute in the water-immiscible phase and lack of interaction between buffer components and solute. Conditions for optimal liquid-liquid extraction of weakly ionizable solutes are more easily recognized. With these techniques, the negative logarithm of the acid dissociation constant (pK'a) and the logarithm of the octanol-water partition coefficient (log P) have been measured for warfarin (pK'a = 5.15 +/- 0.04; log P = 2.82 +/- 0.06), strychnine (pK'a = 8.29 +/- 0.02; log P = 2.23 +/- 0.04), phenol (pK'a = 9.88 +/- 0.02; log P = 1.75 +/- 0.05), procaine (pK'a = 8.11 +/- 0.04; log P = 1.10 +/- 0.08), and ephedrine (pK'a = 9.92 +/- 0.01; log P = 1.65 +/- 0.04) at 21 degrees C.

Effect of thioacetamide-induced hepatic necrosis on the regioselective metabolism of S-warfarin by rat liver mixed-function oxidase enzymes.

The biotransformation of S-warfarin was examined using liver microsomes prepared from rats 6-96 hr after treatment with a necrotizing dose (5.6 mmoles/kg) of thioacetamide. Four catalytically distinct classes of enzyme activity were observed which declined in activity with different half-lives after thioacetamide intoxication. S-Warfarin 7-hydroxylase activity was destroyed with a half-life of 16.6 +/- 3.1 hr. 6-Hydroxylase activity was destroyed with a half-life of 25.3 +/- 3.0 hr. 4'-Hydroxylase activity was destroyed with a half-life of 34.6 +/- 4.8 hr, which paralleled the loss of total hepatic cytochrome P-450 with a half-life of 33.4 +/- 3.6 hr. Production of an unidentified metabolite was not affected by thioacetamide intoxication during the first 48 hr. The ratio of rates of product formation were used as an alternative method to test the homogeneity of distinct enzyme catalytic activities. The ratio of measured responses (e.g. chromatographic peak heights) was used directly to determine the product ratios, provided that the rate of formation of each product was directly proportional to the experimentally measured response for each product. The use of product response ratios to discriminate between catalytic activities was inherently more precise because calibration errors were eliminated. Differences in the rates of destruction of warfarin hydroxylases provided further evidence of the multiplicity of hepatic mixed-function oxidases and suggested topographical differences in their location within the liver lobule.