The inhibitory effect of carrageenan-induced inflammation was examined by utilizing rats treated with inducers of this drug metabolizing system. Animals were given sodium phenobarbital (PB, 80mg/kg, i.p., 24h prior to death), or benzo [α] pyrene (BP, 40mg/kg, i, p., 24h prior to death) as inducers. Some animals were also given carrageenan 24 h prior to death. Non-induced male rats exhibited significant decreases in hepatic 9000×g supernatant (S-9) cytochrome P-450 and aminopyrine (AM) N-demethylase, benzphetamine (BenzP) N-demethylase and meperidine (MP) N-demethylase activity following carrageenan treatment. Carrageenan also depressed the induction of hepatic S-9 cytochrome P-450 content caused by PB treatment, and suppressed the induction of AM, BenzP, MP, arylhydrocarbon and 7-ethoxycoumarine metabolism by PB treatment. Cytochrome P-450 levels and related biotransformation activity which are elevated by BP treatment were not decreased by the injection of BP and carrageenan simultaneously to male rats. Non-induced, PB-treated and BP-treated female rats did not show inhibited carrageenan-induced reduction in hemoprotein content or inhibition of AM-N-demethylase, BenzP N-demethylase and aniline hydroxylase activities. These results demonstrate the selective nature of the inhibitory effects of carrageenan-induced inflammation upon drug metabolism in the rats.

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After oral administration of ricin in rats, its distribution in the gastrointestinal tract, body fluids and principal organs was determined by an enzyme immunoassay, and the immunoreactive ricin detected was identified by gel filtration followed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, protein blotting and the immunobinding method. When ricin D (10mg/kg rat) was given orally to a rat, which dose is equivalent to 1/3 LD₅₀, about 75% of the ricin was found in the stomach and small intestine within 2h, and most of it was transferred to the large intestine after 24h. It was also demonstrated by an in vitro toxicity test of immunoreactive ricin in the blood and lymph obtained from the intoxicated rats that a part of the ricin was absorbed from the small intestine into the tissues and organs via the circulatory systems (lymphatic and blood vessels) as the active ricin. The participation of the blood vessels was greater in the absorption of ricin from the gastrointestinal tract than that of the lymphatic system. Ricin, after absorption, was detected in liver and spleen and ricin found in the liver was predominantly in the form of intact ricin, although an undetectable amount of ricin in other organs cannot be eliminated. These results infer that a small fraction of orally-given ricin was transferred to the circulating system and was responsible for rat's death as in the case of i.p. administration.

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The compartmental model analysis by use of simultaneous curve fitting was carried out to ascertain the pharmacokinetic relationship between amitriptyline (AMT) and nortriptyline (NRT) in the serum and brain after acute or chronic oral administration of AMT. The estimated F value, a fraction of dose reached at systemic circulation, and the M_D value, a fraction metabolized to NRT, were 0.044 and 0.020, respectively, after acute administration, indicating first-pass metabolism of AMT. The estimated parameters k_in and k_out, the transfer rate constants to and from the brain, showed no marked difference between AMT and NRT. These findings indicate equivalent ability of AMT and NRT to penetrate into the brain. The area under the concentration curve (AUC) values of AMT and NRT in the serum increased 1.4 and 8.2 times, respectively, with the increase of NRT being greater after chronic administration. The M_D value was increased from 0.020 to 0.096, whereas the estimated F value showed no marked change. These results indicate the enhanced first-pass metabolism. The estimated transfer rate constants k_in and k_out of AMT were close to those of NRT. In addition, the transfer rate constants after chronic administration were similar to those after acute administration, indicating no marked change in penetration into the brain by multiple dosing.

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The disposition of quinidine was investigated in rats with experimental hepatic disease caused by an intraperitoneal injection of CCl₄. The plasma disappearance of quinidine after a 12.5 mg/kg i.v. bolus injection was analyzed by a two-compartment open model in both control and CCl₄-intoxicated rats. In the CCl₄-intoxicated rats, plasma total body clearance (CL_tot), elimination rate constant of the central compartment (K_el) and the volume of distribution (V_dss) of quinidine were decreased by 73, 51 and 36%, respectively, compared to those in the control rats. At a steady state of quinidine plasma concentration of 1μg/ml, tissue-to-plasma partition coefficient (K_{p, vivo}) of the drug in the lung, spleen, heart, kidney and liver in the CCl₄-intoxicated rats were decreased ranging from 32 to 42% compared to those in the control rats. The plasma free fraction of quinidine in the intoxicated rats was decreased by 34% of that in the control rats. Neither tissue binding of quinidien in vitro, nor plasma pH was altered in the intoxicated rats. Thus, the decrease in V_dss and K_{p, vivo} for quinidine in the intoxicated rats seems likely to be due to an increase in plasma protein binding of the drug. Metabolic activity in the liver, the hepatic extraction ratio for quinidine, and the hepatic blood flow in the CCl₄-intoxicated rats were decreased by 84, 57 and 47%, respectively, compared to those in the control rats. The decrease in CL_tot and K_el in the intoxicated rats is considered to be attributed to both the reduction of liver functions and the increase in the plasma protein binding of the drug.

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The specific binding of insulin to diaphragm and flexor digitorum brevis (FDB) muscles isolated from diabetic KK-CA^y and streptozotocin (STZ)-diabetic ddY mice was investigated under high glucose concentration in vitro. For high-affinity insulin receptor under 2.8 mM glucose, amounts of the receptor and values of dissociation constant (K_d) were greater in both diabetic muscles than in the corresponding normal control muscles, respectively. High glucose concentration up to 16.7 mM reduced both the up-regulation of the receptor and the decrease in the affinity by the diabetic state. These studies strongly suggest that high glucose level in the diabetic state in vivo may suppress the up-regulation of high-affinity insulin receptor in both models of diabetic mice.

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In order to clarify the involvement of phosphatidylserine (PhS) in the cellular accumulation of propranolol, we have characterized the binding of ³H-propranolol to cultured rat fibroblasts and to liposomes containing PhS. The properties of propranolol binding to the cells and liposomes were analyzed by means of a Scatchard plot. The cells contained at least two classes of propranolol binding sites, one site of high affinity/low capacity and the second site of lower affinity/higher capacity, while the liposomes contained only one class of binding site. The values of the association constant (K) and number of binding sites (n), given on a PhS basis for the propranolol binding site in the liposomes, were both very close to those of corresponding binding parameters for the high affinity/low capacity binding site in the cells. Cell death, caused by various toxic reagents, resulted in a marked decrease in propranolol accumulation in the cells. Kinetic analysis of the drug binding to dead cells showed one binding site with binding parameters comparable to those of the low affinity/high capacity binding site in the intact cells. Polar cations, methylamine and NH₄Cl, completely inhibited propranolol binding to the liposomes. On the other hand, these cations partially inhibited propranolol accumulation in intact cells and failed to inhibit the drug binding to dead cells. These results suggest that PhS in cytomembranes represents the high affinity/low capacity propranolol binding site in cultured rat fibroblasts.

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