A physiologically based model for drug reabsorption in renal tubules was applied to sulfanilamide reabsorption kinetics in rats, rabbits and dogs. The reabsorption percent of sulfanilamide decreased with an increase of urine flow rate in the three animal species examined. Furthermore, the reabsorption percent increased with the decrease of the glomerular filtration rate (GFR), even though the urine flow rate normalized by GFR was the same. The power law formula was obtained between AR (l). Pe and the animal body weight. The power was 0.721, which was less than unity. In contrast, σ was not dependent on animal body weight. The reabsorption percent of sulfanilamide in man was calculated using AR (l) Pe and σ obtained from animal data. The value thus calculated was 50-60%, which was comparable to the reported value (52%) in healthy human subjects. Therefore, the reabsorption percent of sulfanilamide in man was successfully predicted by the extrapolation of animal data.

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The effects of valproic acid (VPA) on pharmacokinetics of cyclophosphamide (CPM) alkylating metabolites were investigated in male BALB/c mice. The pharmacokinetics of CPM alkylating metabolites was found to be dose-dependent representing the decrease of formation and elimination rates of the metabolites. A nonlinear increase of area under blood concentration of CPM alkylating metabolites-time curve (AUC) occurred with increasing CPM dose of 100, 200, and 300 mg/kg body weight. The effects of VPA (100 mg/kg dose) coadministered with CPM were similar to those of the increase of the CPM dose in preventing the activation of CPM and the elimination of its alkylating metabolites. The delayed disposition of CPM alkylating metabolites resulted in a 1.5-fold increase (p<0.02) of AUC which was considered the most important pharmacokinetic parameter in the CPM therapy. VPA which was injected i. p. at a dose of 100, 200, or 300 mg/kg increased the pentobarbital induced-sleep time by 81, 138, or 192%, respectively. In order to assess the effect of VPA on drug metabolizing enzyme (s) activity in humans, the ratio of daily urinary 6-hydroxycortisol to 17-hydroxycorticosteroids, which can reflect cytochrome P-450 activity, was determined in 5 healthy volunteers. The ratio was rapidly and significantly decreased (p<0.05) and this reduction continued during VPA administration. These findings and those reported in the literature concerning CPM metabolism suggest that the delay of CPM alkylating metabolites elimination resulted in part from microsomal enzyme (s) inhibition by VPA.

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Phthalidyl theophylline (PH-TH) in rat liver was metabolized by a hydrolase to theophylline (TH) and 2-carboxybenzaldehyde, and the latter was further metabolized to 2-hydroxymethylbenzoic acid by an nicotinamide adenine dinucleotide-dependent reductase. The hydrolase could be strongly inhibited by acetazolamide, therefore, urinary excretion of PH-TH metabolites was significantly retarded when PH-TH and acetazolamide were coadministered to rats. The results from in vivo experiments suggest that PH-TH was efficiently absorbed from the gastrointestines and metabolized extensively by the liver.

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The influence of food on the bioavailability of mefenamic acid from two commercial capsules (products A and B) differing in bioavailability was studied with four healthy male volunteers. The drug was administered as a single oral dose of 250 mg under fasting and nonfasting conditions. The study used a 4×4 Latin-square design. Seven blood samples were collected over a 9-h period following administration and the plasma concentrations of mefenamic acid were determined by a high performance liquid chromatographical method. The bioavailability was significantly different between the two products in the fasting condition, agreeing with the result of an in vitro dissolution study. However, in the nonfasting state, the difference was not significant because the product showing poor bioavailability, product A, in the nonfasting state showed marked improvement. On the other hand, the product showing good bioavailability, product B, was not affected by food.

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A new version of MULTI (ELS) written in BASIC was presented for population pharmacokinetics for microcomputers. The program is provided with four algorithms of extended nonlinear least squares (steepest descent method, quasi-Newton method with DFP formula, quasi-Newton method with BFGS formula and simplex method). Four transformations of parameters can be selected to impose constraints on the parameters (no constraint on a parameter. Pi=Qi², Pi=B+(A-B)·sin² (Qi) and Pi=B+(A-B)·exp (Qi)/(1+exp (Qi)), where Pi denotes a population mean parameter or variance of inter-and intraindividual variations, Qi is a intermediate parameter, A and B are lower and upper limits of Pi. The definition of a population model and the modifications for BASIC compiler in the new version of MULTI (ELS) are the same as in the old version.

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The main pharmacological effects and acute toxicity of nicergoline (NCG, ester type), its 5 metabolites [1-DN (ester type), 1-MMDL, 1-OHMMDL, MDL (ergolinealcohol type) and 5-BNA (bromonicotinic acid)], 2 decomposition products (1-MMDL and 5-BNA) and 2 impurities [1-DN and 5-CN (ester type)] were studied in animals. 1. In mice, the acute intraperitoneal toxicity of 1-MMDL, 1-OHMMDL and 5-CN was similar to that of NCG (LD₅₀ 197.6 mg/kg). The toxicity of 1-DN, MDL and 5-BNA was approximately 2-fold, 2-fold and one half of NCG, respectively. These substances caused no delayed death. 2. In protective effects against KCN-and adrenaline-induced death in mice when given i. p., 1-DN and 1-MMDL were less potent than NCG, and 1-CN was similar in potency to NCG. In competitive inhibitory effects on phenylephrine-induced contraction of isolated guinea pig vas deferens, 1-DN was less potent, 1-MMDL was much less potent and 5-CN was more potent than NCG. In an inhibitory effect on collagen-induced platelet aggregation in vitro using rat platelet-rich plasma, 1-DN and 5-CN were similar in activity to NCG and 1-MMDL was less active than NCG. On the other hand, 1-OHMMDL, MDL and 5-BNA were inactive in these experiments. 3. In experiments on gross behavior, motor function and barbital anesthesia using mice, when given i. p., 5-CN as well as NCG moderately induced depressive effects on the central nervous systems. 1-DN and 1-MMDL were less potent in the effects than NCG. In anesthetized rats, when given i. v., 1-DN and 5-CN dose-dependently caused lowering effects on blood pressure similar to NCG. 1-MMDL and 1-OHMMDL were less potent than NCG in the lowering effect. 1-DN and 5-CN moderately decreased the contractile force in the isolated guinea pig heart when given i. a. 5-CN alone decreased urine volume in rats when given i. p. and all the substances had no effect on the intestinal transit ability in mice when given i. p. 4. These results suggest that the pharmacological effects of NCG are due to NCG per se and in part to its metabolites. As regards structure-activity relationships, NCG, 1-DN and 5-CN with an ester linkage were found to be more potent in pharmacological activities than ergoline-alcohol compounds. However, the pharmacological effects of NCG when used in humans do not appear to be affected by 1-DN and 5-CN because these impurities in the tablets of NCG are found in negligible amounts.

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The release of slow reacting substance of anaphylaxis (SRS-A) by antiimmunoglobulin E (IgE ; ∈)-antibody mediated passive peritoneal anaphylaxis (PPA) in rats was investigated immunopharmacologically. 1) A significant amount of SRS-A was released by anti-∈-antibody in the peritoneal cavity of rats passively sensitized with IgE. The amount of SRS-A released by anti-∈-antibody was about one third less than that released in an anti-γ-antibody and IgG_2a system. 2) The release of SRS-A was initiated at 2 min and reached its maximum 5 to 10 min after the injection of anti-∈-antibody. 3) Disodium cromoglycate, tranilast and ketotifen inhibited the release of both SRS-A and histamine caused by anti-∈-antibody mediated PPA. 4) Glucocorticoids (hydrocortisone, prednisolone and dexamethasone) also inhibited the release of both mediators. 5) p-Bromophenacyl bromide inhibited the release of both mediators. AA-861, a potent 5-lipoxygenase inhibitor, inhibited the release of SRS-A but not histamine. 6) Indomethacin slightly enhanced the release of SRS-A and inhibited the release of histamine. 7) Cytarabine resulted in leucopenia and inhibited the release of histamine but not SRS-A during PPA. 8) Dextran sulfate reduced the number of glass adherent peritoneal cells and inhibited the release of SRS-A but not histamine. These results suggest the suitability of anti-∈-antibody mediated rat PPA for investigating the effect of anti-allergic agents on the release of SRS-A.

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Ca efflux from sarcoplasmic reticulum (SR) of a skinned skeletal muscle fiber was measured quantitatively using ⁴⁵Ca. The time course of Ca efflux was fitted by superimposing two exponential curves. Caffeine caused Ca efflux from SR at very low concentration of free Ca ion. In order to study the relation of the Ca efflux mechanism to Ca-induced Ca release, caffeine was introduced to SR under controlled free Ca concentration. The results showed that caffeine induced Ca release from SR.

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