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The pharmacokinetics, distribution, plasma protein binding and the biliary excretion of pinazepam were studied in the rat. The drug was administered (5 mg/kg) by i.p. injection. The chemical analysis of pinazepam and its metabolites was carried out by a gas-chromatographic method. The parent compound was rapidly absorbed, accumulated into the tissues and converted into N-desmethyldiazepam. The highest plasma levels of the parent compound (367 +/- 13 ng/ml) were found 3 min after administration. The volume of distribution and the clearance of the drug were 1315 ml and 7.23 ml/min respectively. The metabolite was detected in the plasma and tissues 3 min after administration. At this sampling time its concentrations were 76 +/- 16 ng/ml in the plasma and 1081 +/- 68 ng/g in the liver. The decay curve of both pinazepam and N-desmethyldiazepam in the plasma, liver, lung, heart, kidney, brain, and gastrochemius muscle were characterized for their Kel, t 1/2, and AUC values. The tissue AUC to plasma AUC ratios indicated a preferential accumulation of pinazepam over its metabolite in the tissues. The plasma protein binding of pinazepam was measured by dialysis at the equilibrium. Rat plasma proteins bound 89.17 +/- 0.20 percent of the drug. The association constant was 2.60 X 10(3) l/mole and the number of sites 0.44 X 10(-6) sites/g. The biliary excretion of pinazepam and N-desmethyldiazepam was poor.

The subcellular distribution of ('H)-styrene-7,8-oxide was studied in the rat liver. The compound was added to liver homogenate to give a final concentration of 2 x lo-'; 2 x lo-' and 2 x lo-' M. Subcellular fractions were obtained by differential centrifugation. Most of styrene oxide (59-88%) was associated with the cytosolic fraction. Less than 15 percent of the compound was retrieved in each of the nuclear, mitochondria1 and microsomal fractions. A considerable percentage of radioactivity was found unextractable with the organic solvents, suggesting that styrene oxide reacted with the endogenous compounds. The intracellular distribution of this epoxide was also studied in the perfused rat liver. Comparable results with those previously described were obtained. The binding of styrene oxide to the cytosolic protein was investigated by equilibrium dialysis and ultrafiltration. Only a small percentage of the compound was bound to protein.

The distribution of pinazepam and its metabolite N-desmethyldiazepam was studied in fetuses of New Zealand rabbits on the 20th and 27th day of pregnancy. The concentrations of both compounds were also measured in the maternal brain, liver and uterus. Pregnant rabbits were sacrificed at 0.5, 2, 4 and 12 h after intravenous administration of pinazepam (5 mg/kg). The concentrations of pinazepam and N-desmethyldiazepam in various biological specimens were measured by a specific gas-chromatographic procedure. Pinazepam and N-desmethyldiazepam rapidly crossed the placenta. In 20 day old fetuses, comparable concentrations of pinazepam were found in the liver, brain, heart, lungs and kidneys. In contrast, the liver of 27 day old fetuses accumulated pinazepam at concentrations higher than the other tissues. The hepatic extraction of pinazepam, already described in adult rabbits (1), develops prenatally. A preferential accumulation of pinazepam rather than N-desmethyldiazepam was also observed in the maternal uterus. In this tissue the concentrations of pinazepam were 5-10 times higher on the 27th rather than the 20th day of pregnancy. The stage of pregnancy influences the distribution pattern of pinazepam in rabbit fetuses and their mothers.

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