The pharmacokinetics of phenytoin (DPH) was investigated in rats with uranyl nitrate induced renal failure, and with D-galactosamine induced hepatic failure. The serum disappearance of DPH after 10 mg/kg i.v. dose followed a two-exponential decline in normal and both types of intoxicated rats. The serum disappearance half-life (t_1/2) and the volume of distribution (V_d) significantly increased in both types of intoxicated rats, while the total blood clearances (CL_b) significantly decreased. The serum unbound fraction (fu) of DPH significantly increased in both types of intoxicated rats. The blood to plasma concentration ratio (R_B) of DPH significantly increased in the uranyl nitrate-treated rats, while that of the D-galactosamine-treated rats did not show significant alteration. The tissue to serum concentration ratios (K_p) of most of tissues studied after i.v. bolus injection of DPH increased in both types of intoxicated rats. Except for the lung of the D-galactosamine-treated rats, the tissue to serum unbound concentration ratio (K_pu) of other tissues did not show a significant alteration. This suggested that the tissue uptake and/or binding of DPH is not affected by uranyl nitrate or D-galactosamine intoxication and that the increases in V_d and K_p are due mainly to the decrease in serum protein binding. The hepatic intrinsic clearance of unbound DPH (CLu_{int, H}) also decreased in both types of intoxicated rats. Thus, the uranyl nitrate and D-galactosamine intoxication caused the increase in fu and the decrease in CLu_{int, H} and these results may explain the significant decrease in CL_b and increases in V_d and t_1/2. The tissue concentration-time courses of DPH were predicted by a physiologically based pharmacokinetic model and good agreement between the predicted and observed values in normal and in both types of intoxicated rats were obtained for serum, liver, kidney, brain and muscle.

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The acetohexamide reductase activity in 10000×g supernatant fluids of kidney homogenates was significantly higher in male than in female rats. Although difference in activity of acetohexamide reductase in the cytosol between the sexes was not observed, the activity in the microsomes was considerably higher in male than in female rats. These findings indicate that the microsomal enzyme plays an important role in the sex difference of acetohexamide reduction by 10000×g supernatant fluids of kidney homogenates. The sensitivities to inhibitors of microsomal acetohexamide reductase were different from those of cytosolic acetohexamide reductase. Furthermore, streptozotocin-induced diabetes significantly decreased acetohexamide reductase activity only in the kidney microsomes of male rats, resulting in the abolishment of the sex difference of acetohexamide reduction by 10000×g supernatant fluids of kidney homogenates.

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The diuretic effect of piretanide, one of the loop diuretics, was investigated in three different hydrated conditions, namely well hydrated condition (treatment I), progressive hydropenic condition (treatment II) and complete hydropenic condition (treatment III) in rabbits. Each rabbit received intravenous administration of 1.5 or 15 mg/kg of piretanide and the urine flow rate, the excretion rates of Na and K, plasma concentrations of Na and K, urine osmolarity, plasma concentration of piretanide and urinary excretion of piretanide were determined after administration. The pharmacokinetics of piretanide was not influenced by the hydration state of the body, even in treatment III. The diuretic effect of piretanide evaluated by both urine flow rate (E_H2O) and Na+K excretion rate (E_Na+K), was significantly affected by the hydration state of the body. The more the hydropenic state was developed, less amounts of urine or electrolytes were excreted. A pharmacokinetic-pharmacodynamic link model which was proposed in the previous paper was applied to the present experimental results. The result indicated that the diuretic effect, even in the complete hydropenic condition (treatment III), was reasonably described by the model, with minor modifications. The time course of the excretion rate of K (E_K) was not always in parallel with E_Na+K, but was dependent on treatments. We found that the K-fraction, which was known as an indicator of the Na-K exchange reaction in the distal tubule, was quantitatively related to E_Na+K, using a simple equation. Accordingly, the time course of E_K was also calculated. The result also indicated that time courses of E_K were described reasonably well by the model, regardless of treatments and doses.

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Comparative studies on the disposition of two pairs of drugs and their prodrugs, i.e., (1) salicylamide (SAM) and ethenzamide (ETB), (2) acetaminophen (NAPA) and phenacetin (PHT), were performed in dogs following intravenous and oral administration of the drugs. ETB and PHT were largely metabolized to SAM and NAPA, respectively, and SAM and NAPA thus formed or those directly administered were conjugated with sulfuric acid and glucuronic acid. It was found that the prodrugs, ETB and PHT, were more susceptible to first-pass metabolism than the corresponding parent drugs, SAM and NAPA, respectively at 30 mg/kg dose of each drug. Free NAPA levels in the blood of dogs receiving PHT were found to be considerably high, whereas free SAM levels in the blood of dogs receiving ETB were very low. These are consistent with results in humans which have been reported earlier, suggesting the similarity between dogs and humans. The ratio of sulfate to the sum of sulfate and glucuronide (S-ratio) as the area under blood concentration-time curve and urine were examined. The prodrugs (ETB and PHT) showed higher Sratios than the corresponding parent drugs (SAM and NAPA). The S-ratios were greater than 0.6 in ETB and SAM and less than 0.5 in PHT and NAPA, indicating that sulfate formation was predominant in the former pair while glucuronide formation was predominant in the latter pair. No intestinal metabolism was found in the prodrugs. In the parent drugs, however, conjugation with sulfuric acid and glucuronic acid was observed. These indicated that the de-ethylation activity in dog intestine was negligible, if any, while activities of the uridine diphosphate-glucuronyltransferase and phenolsulfokinase were appreciably high.

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Various factors influencing corneal permeability to bunazosin were investigated. The permeability of the cornea to bunazosin increased with increasing pH, either in the presence or absence of caprylic acid ; the permeability to bunazosin and the partition of bunazosin were both enhanced by caprylic acid and both enhancements became maximal when the molar ratio of bunazosin : caprylic acid became unity ; the permeability to methylparaben, a non-ionic permeant, was not increased by caprylic acid or capric acid and the permeability was not increased by the pretreatment of the cornea with caprylic acid. Furthermore, protein-bunazosin interaction was not affected by caprylic acid. The present results suggest that the enhancement of permeability caused by caprylic acid is attributable only to the increased partition of bunazosin to the corneal membrane.

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There has been a considerable increase in popularity of the NONMEM method as a technique for estimating population pharmacokinetic parameters. The authors present another approach to population pharmacokinetic analysis, the alternative two stage method (ATS). ATS uses the EM-algorithm for maximizing the likelihood of variance components. The performance of ATS was compared with the NONMEM method on a microcomputer. Simulation studies showed that the precision and accuracy of estimates obtained with ATS were comparable to the NONMEM method, however, the computation time, dependences on initial estimates and convergence properties were somewhat different. ATS could be a valuable alternative to the NONMEM method for estimating population pharmacokinetic parameters in some cases.

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In order to avoid first-pass metabolism and to maintain therapeutically effective concentration of propranolol (PL) for a prolonged time, ointments of PL were prepared and the percutaneous (p.c.) absorption was investigated in rabbits. To describe the plasma PL concentration profile during repeated p.c. administrations, a simple pharmacokinetic model, including a first-order absorption process, was applied. The p.c. absorption of PL from both macrogol (400 : 4000, 30 : 40, g/g) and Carbopol 934 ointments was significantly increased by adding Azone^[○!R] (AZ). Effective plasma levels were sustained for about 10-20 h, but the absorption of PL from the macrogol ointment was relatively slow. The bioavailability of PL in the 5% PL Carbopol ointment with AZ was 13%. The plasma level of PL after application of Carbopol ointment was enhanced as PL was increased in the ointment, 3 to 5%. The repeated p.c. absorption studies were carried out by applying the 5% PL ointment daily for 3 d. The use of the pharmacokinetic model was justified by good agreement with the observed data after repeated applications of the ointment. Thus, the plasma PL concentration profile during repeated p.c. administrations can be predicted using the model.

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The inhibitory activity of N-substituted derivatives of moranoline (1-deoxynojirimycin) against intestinal α-glucosidase and postprandial hyperglycemia was evaluated. None of the N-substituted derivatives studied displayed more potent inhibition of sucrase or maltase from rabbit intestines than the parent compound moranoline. However, unlike the in vitro results, many compounds exhibited more potent hypoglycemic activities than moranoline in sucrose-, or starch-loaded rat models. Alkenyl or aralkenyl derivatives displayed more potent hypoglycemic activities than alkyl or aralkyl derivatives. There was a weak correlation between in vitro and in vivo assay systems found by statistical analysis. It is necessary to evaluate compounds in vivo in order to select the most potent hypoglycemic compound.

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We concluded that a neutral subfraction of mannan from bakers' yeast (Saccharomyces cerevisiae wild type strain), abbreviated as WNM, was able to induce the release of leukotrienes from mouse peritoneal macrophages (Mφ). The culture supernatant fluid of Mφ from normal mice cultured with WNM caused a marked contraction of guinea pig ileum. This activity was inhibited by pretreatment of Mφ with inhibitor of phospholipase A₂ or lipoxygenase before Mφ were treated with WNM, and by treatment of the incubation bath with a slow reacting substance antagonist, FPL55712. On the other hand, pretreatment of Mφ with a cyclooxygenase inhibitor potentiated contractile response of ileum by culture supernatant fluid of Mφ. A high performance liquid chromatographic analysis of a culture supernatant fluid of Mφ treated with WNM demonstrated the presence of leukotrienes C₄ and D₄, and their related compounds.

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Several alkyl ester derivatives or α-monoglyceride derivatives of ³H-labeled compounds, i.e. trimetoquinol, TA-594, acetaminophen, naproxen and nicotinic acid, were synthesized and administered orally to rats cannulated in the thoracic duct. The radioactivity appearing in 24 h-lymph was measured and analyzed by thin-layer chromatography. Most of the α-monoglyceride derivatives were absorbed via the intestinal lymphatic system, while the alkyl esters were very poorly absorbed. After oral administration of α-monoglyceride derivatives of labeled naproxen and nicotinic acid, the radioactive compounds found in the lymph were mainly monoglyceride, diglyceride and triglyceride analogues, while in plasma the main radioactive compound was the parent drug. It was concluded that α-monoglyceride derivatives of drugs were absorbed via the lymphatic system and transported into blood, yielding the parent drug in blood.

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Forskolin-activated adenylate cyclase activity in rat erythrocyte membranes was markedly inhibited by methanol in a concentration dependent manner. On the contrary, no change was observed in the basal cyclase activity in the presence of methanol. The methanol inhibition forskolin-activated cyclase activity was protected by the stimulation of Gs in the presence of NaF in a concentration dependent manner. These data indicate that low-and high-affinity binding sites of forskolin in rat erythrocyte membranes have different sensitivities to methanol.

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