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UV and fluorescence spectrophotometry were used to establish the analytical profile of a potent myotonia inducer, anthracene-9-carboxylic acid (I). UV spectrophotometry is useful for the determination of I when it is dissolved in physiological solutions (Ringer's, Tyrode's, etc). In these fluids there is a linear relationship between UV absorption and I concentration between 500 and 2000 ng/ml (2.25-9.0 X 10(-6)M). However, in biological fluids there are interferences in the UV absorption due to organic substances. On the other hand, fluorescence spectrophotometry is more sensitive than UV for determinations in plasma and urine. Within the range of 200-1000 ng/ml (0.9-4.5 X 10(-6) M) fluorescence intensity increases linearly with concentration. Furthermore, when both emission and excitation spectra are combined there are no interferences due to organic substances normally present in those fluids. An extraction procedure of I from plasma and urine is also described, and the importance of I determinations in relation to the problem of this myotonia-inducing aromatic monocarboxylic acid is discussed.

The clinical kinetics of 1, 4-dihydroxy-5,8-bis[[ 2-[(2-hydroxyethyl) amino] ethyl] amino]-9,10-anthracenedione dihydrochloride (DHAQ) are reported. DHAQ, 1 to 3 mg/m2, was administered as an intravenous bolus to six patients with metastatic cancer. Plasma clearance of the drug followed a biphasic pattern with a harmonic mean initial half-life (t 1/2) of 13.7 min and a terminal t 1/2 of 37.4 hr. Recovery of unchanged drug in the urine was 6.8% at 24 hr and 7.3% at 72 hr, while the corresponding recovery of total radioactivity was 9.4% and 11.3%. Apparent volume of distribution of DHAQ was about 13.8 +/- 2.9 l/kg. Total clearance was 238.7 ml/kg/hr, twice the creatinine clearance.

After single intracaecal administration of [14C]rhein (25 mg kg-1) and [14C]rhein anthrone (20 mg kg-1) to rats, the summated recovery rates of 14C after five days were in urine 37(+/- 8.3)% and 2.8(+/- 0.4)% and in faeces 53(+/- 9.5)% and 95 (+/- 10.1)%, respectively. The clearance of radioactivity from the organs and tissues was almost complete within three days, with the exception of the kidney which exhibited pronounced retention of radioactivity even after five days (less than 61% of 24 h values). Extracts of faeces from animals treated with [14C]rhein of [14C]rhein anthrone, revealed rhein as well as other radioactive substances, which chemically did not react as 1,8-dihydroxyanthraquinones.

The new antidepressant agent oxaprotiline is extensively metabolized by man. Following an oral 50 mg dose of racemic [14C]oxaprotiline, most of the 14C was excreted in the urine as metabolites (greater than 98% total 14C); only 1% was excreted unchanged. Glucuronidation at the carbinol group of the molecule is the major metabolic pathway (83%). The two diastereoisomeric glucuronides were separated; the more polar O-glucuronide of S(+)-oxaprotiline predominates (44%), suggesting stereoselective disposition of the two enantiomers. Oxidative pathways are minor, and yield desmethyl oxaprotiline (10%) and 3-hydroxy R(-)-oxaprotiline (4%), both of which are conjugated with glucuronic acid. The biotransformation of oxaprotiline in man is less complex than that of other polycyclic antidepressants, which are metabolized mainly by oxidative reactions.

The pharmacokinetics of anthracene-9-carboxylic acid (9-AC), a potent myotonia-inducer, was determined in 9 New Zealand White male rabbits after the intravenous injection of 36 microM X kg-1. Myotonic contractions appeared 30 to 80 sec after the beginning of injection. One minute after injection, 25% of the administered dose remains in the blood (9-AC in plasma + 9-AC in cells). Of the 9-AC present in whole blood, 78% is in plasma and can be totally extracted with chloroform whereas the remaining 22% is in the blood cells and can not be extracted. The disappearance of 9-AC from plasma can be explained numerically by assuming an open two-compartment model. By means of a non-linear regression analysis the equation Cp = 20.65e-0.3216t + 28.35e-0.0147t was obtained. This equation gives the best fir for the mean values of all the experiments. The equilibrium between the two compartments is reached in 9.0 min and the Vdss X kg-1 at this time is equal to 273 +/- 18.6 ml X kg-1 which is only marginally larger (10%) than the estimated extracellular volume (246.0 ml X kg-1), suggesting that 9-AC barely penetrates into the cells. The plasma concentration values at t1/2e1 and 3t1/2e1 are 1.07 X 10(-4) M and 2.69 X 10(-5) M, respectively. Similar concentration values were found by other authors as capable of reducing the chloride conductance of skeletal muscle membrane and producing myotonia in vivo and in vitro. Thus, there is a good correspondence between the concentrations active in vitro and the concentrations of plasma in vivo found in this study. Other pharmacokinetic parameters are: t1/2 alpha = 2.8 +/- 0.3 min; t1/2 beta = 45.7 +/- 2.2 min; Area under the curve (AUC) = 1920 +/- 125.0 micrograms X min X ml-1; K12 = 0.085 +/- 0.01 min-1; K21 = 0.162 +/- 0.02 min-1; t1/2e1 = 28.84 +/- 2.2 min., and V1 X kg-1 = 172.1 +/- 9.7 ml. All our findings plus the rapid appearance of myotonic signs and the correspondence with the in vitro studies support the previous assertion that 9-AC acts on the cellular membrane of the skeletal muscles.

Recovery from urine of the mutagenic activity of 2-anthramine, cyclophosphamide, 7,12-dimethylbenz[a]anthracene, 6-chloro-9-((3-(2-chloroethylamino)-propyl)amino)-2-methoxyacridin e dihydrochloride (ICR-191), mitomycin-C, nitrofurantoin, and quercetin was studied with several of the Ames tester strains using acetone-extracted XAD-2 columns with yields ranging from 27% to 79%. Dose responses of the pure chemicals were also studied, and results showed TA 97 to be far more susceptible to quercetin mutagenesis than TA 1537. Reducing pour plate agar volume enhanced mutagenesis.