The metabolites of sodium bisulfite in rabbits through intravenous injection were examined according to the high performance liquid chromatography method for determination of sulfurcontaining substances. Most of the administered sulfite was oxidized to sulfate, and a small part was converted to thiosulfate, S-sulfoalbumin, S-sulfoglutathione and S-sulfocysteine. Furthermore, it was found that S-sulfocysteine administered intravenously to a rabbit was partially changed to inorganic sulfate and thiosulfate. These metabolites produced from sulfite in rabbits indicated the presence of the many and complicated metabolic pathways of sulfite in vivo.

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In order to clarify the possibility of pharmacokinetic interaction between quinolone and fenbufen, the plasma concentration-time profiles and serum protein binding of enoxacin, fenbufen and its active metabolite, felbinac, were investigated in rats. The rats were administered an intravenous dose of enoxacin (5 mg/kg) and fenbufen (10 mg/kg) alone or concomitantly. Coadministration with fenbufen tended to prolong the plasma elimination half-life of enoxacin by about 20%, whereas it showed no effect on the area under plasma concentration-time curve, total body clearance or distribution volume of enoxacin. The extent of enoxacin binding to rat serum tended to be slightly reduced by fenbufen in vivo and in vitro. Plasma concentration-time curves, pharmacokinetic parameters and serum protein binding of fenbufen and felbinac were not affected at all by the coadministration with enoxacin. These aspects suggest that there may be only a minor possibility of the pharmacokinetic interaction between enoxacin and fenbufen.

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In order to quantify the renal handling of iodopyracet (IOD) and sulfamethizole (SMZ), single-drug clearance studies in rabbits were performed under quasi-steady state conditions with stepwise increasing the infusion rate of IOD or SMZ. Although concentration dependence of plasma protein binding was observed for both drugs, the urinary excretion rate of IOD was proportional to its total plasma concentration at low total plasma concentrations of 0.05-0.8 mM. On the other hand, the relationship between urinary excretion rate and total plasma concentration of SMZ was a concave-ascending curve at low plasma concentrations and the renal clearance of SMZ was sensitive to changes in plasma protein binding. However, renal clearances referenced to unbound plasma concentration at total plasma concentrations of 0.05 mM for IOD and SMZ were 9.5 and 38 l/h, respectively. Those values were much greater than the effective plasma flow in rabbits. These facts indicated that the intrinsic clearances at the sites of tubular secretion were high and that the rates of secretion were fully or partially limited by the renal plasma flow. Furthermore it was suggested that unbound drug was liberated from plasma protein at the sites of tubular secretion. The data obtained at high plasma concentrations indicated that the tubular secretion of IOD had capacity limited characteristics and that the urinary excretion of SMZ involved tubular reabsorption as well as saturable tubular secretion. From the data obtained, a perfusion-limited pharmacokinetic model was constructed characterizing the excretory processes, namely, glomerular filtration, passive tubular reabsorption, saturable tubular secretion and reequilibrium between bound and unbound drugs in plasma. For both drugs, the estimates for bulk flow rate were reasonable values of effective renal plasma flow and the dissociation constants for tubular secretion agreed well with those for in vitro renal cortex accumulation, suggesting that the kinetic model based on physiological concepts was useful for the understanding of the drug elimination processes.

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In order to evaluate dose-dependent sulfamethizole (SMZ) kinetics, 100, 300 and 1000 mg of SMZ was constantly infused over 5 min in rabbits and thereafter plasma and urine samples were collected at convenient intervals. When a dose of 100 mg was given, the time course of total plasma concentration followed a biexponential characteristic. For higher doses, plasma decay curves revealed a convex descending feature after the distribution phase. The respective unbound fraction in plasma (f_p) at the total plasma concentrations of 200 and 100 μg/ml were 0.41 and 0.19. The corresponding total body clearances were 2.6 and 2.2 l/h, indicating that the drug elimination did not contribute to the convex-descending plasma curves. A physiologically based pharmacokinetic model was adapted to various tissue levels of SMZ. No saturable tissue binding was observed and the apparent volume of distribution of SMZ at steady state with a rabbit of 3.3 kg, V_ss (1), calculated by tissue volumes and partition coefficients of tissue to unbound plasma was expressed as follows : V_ss=0.14+1.86f_p. From this relationship, it was shown that the apparent volume of distribution of SMZ was significantly affected by the unbound fraction in plasma and the dose-dependent kinetics after intravenous administration was due to the decrease of the apparent volume of distribution with time. The tissue distribution study contributed significantly to the understanding of the dose-dependent drug kinetics.

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The effect of tolbutamide (TB) on the urinary excretion of sulfamethizole (SMZ) under constant infusion of SMZ at 100 mg/h was studied. Intravenous administration of TB (50 mg/kg) caused a decrease in the urinary excretion rate of SMZ but an increase in the unbound concentration of SMZ in plasma. The total concentration of SMZ in plasma decreased rapidly after TB injection and then increased gradually to a level higher than the control. The slope of the terminal phase of the unbound concentration of TB in plasma in the presence of SMZ was significantly smaller than that of TB alone. The analysis using the perfusion limited model showed that the elimination kinetics of SMZ in the presence of TB could be described by the mutual displacement of plasma protein binding of both drugs and the competitive inhibition of the tubular secretion of SMZ by the unbound concentration of TB in renal vein. Further, the inhibitor constant was in good agreement with that for the in vitro uptake by renal cortex slices.

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The effect of a new polystyrene-based, strongly basic, anion-exchange resin possessing an ω-oxobutyl chain as a spacer arm on the fecal bile acid excretion was investigated in rats and compared with that of Dowex 1-X2, chemically equivalent to cholestyramine. The new resin did produce a significant rise in the total fecal bile acid excretion with its ingestion for a period of 4 weeks. Its promoting activity proved to be 2.0- and 1.8-fold more potent than that of Dowex 1-X2 at the 3rd and 4th week, respectively. These results suggest that the introduction of a spacer arm between the polymer backbone and a functional group would lead to an improvement in the in vivo adsorptive efficiency of the resin.

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The metabolism of strychnine was studied with hepatic microsomes of rats, mice, guinea pigs, rabbits and dogs, using high-performance liquid chromatography. Eight metabolites were found by the incubation with rabbit liver microsomes. Five of them were identified as strychnine N-oxide (St N-oxide), 2-hydroxystrychnine (2-OH St), strychnine 21, 22-epoxide, 16-hydroxystrychnine (16-OH St) and 18-oxostrychnine by comparing the chromatographic and spectral data to those of authentic samples. Significant differences in metabolic profiles of strychnine were observed among the above species. The main metabolite in rats and mice was 16-OH St, while in guinea pigs and rabbits, and in dogs, it was 2-OH St, and St N-oxide, respectively. The metabolic activity in guinea pig liver microsomes was much higher than those of other species. There seems to be a fairly good inverse correlation between the metabolic activity and strychnine toxicity in guinea pigs and other animal species.

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Two physiologically based pharmacokinetic models A and B incorporating enterohepatic recycling, which succeeded previously in predicting the disposition of glycyrrhizin (GLZ) in normal rats and subjects, were applied to predict GLZ disposition in plasma and tissues of chronically CCl₄-intoxicated rats, and serum of humans with hepatitis after i.v. dosing. The prediction by model A with the direct excretion of GLZ from liver into gut lumen gave fairly good agreement with the observed time courses of GLZ concentrations in blood and tissues in the intoxicated rats. The human serum disposition was predicted by model B, to which was added a gallbladder for the excretion from liver into gut lumen to model A by assuming continuous delaying transfer from the gallbladder. An attempt to predict the serum dispositions in five human subjects by considering individual differences in serum free fraction, biliary excretion ratio, and intestinal absorption clearance was successful in model B. Thus, scale-up of the disposition kinetics of GLZ from rat to man with liver failure was successful.

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The relationship of the transports between acidic drugs and monocarboxylic acids through the blood-brain barrier (BBB) was examined using the carotid artery injection technique in rats. The BBB uptakes of [³H] acetic acid and [¹⁴C] salicylic acid were significantly reduced by the presence of the respective unlabeled compounds, valproic acid, lactic acid, benzoic acid, nicotinic acid or β-lactam antibiotics (benzylpenicillin, propicillin and cefazolin), but was not reduced by choline, phenylalanine and a basic drug, eperisone. A remarkable pH dependency was observed for the BBB uptake of [¹⁴C] salicylic acid at the pH region of 4.0 to 7.4. Interestingly, 10 mM of salicylic acid diminished significantly the pH dependent BBB uptake of [¹⁴C] salicylic acid. Similar results were obtained in the BBB uptake of [¹⁴C] nicotinic acid. No significant difference was observed in the transport of monocarboxylic acids through the BBB between normotensive Wistar KY rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). From these observations, acidic drugs could be transported by a carrier-mediated system for monocarboxylic acids at the BBB and the transport system was not changed by the disease state.

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