Response function, which correlates pharmacologic response intensity and the drug concentration, is defined assuming that the biophase (or the site of action) is consisted of the elements responsive to the drug, each of which is in a responding or non-responding state depending on the drug concentration in the biophase. The Hill equation, which has been widely used without a definite rationale, for correlation between pharmacologic response intensity and drug concentration is revealed as an approximate equation of the response function. Diuretic data obtained after administration of furosemide and reported previously are used for conformity assessment of the response function.

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Positive inotropic and renal vasodilatory effects of a novel dopamine prodrug, docarpamine, [N-(N-acetyl-L-methionyl)-3, 4-bis (ethoxycarbonyl) dopamine ; TA-870] and those of levodopa were compared in anesthetized dogs, and emetic effects of the two drugs were compared in conscious dogs. Intraduodenal administrations of docarpamine and levodopa at 20 mg/kg produced similar increases in cardiac contractility. The maximal increases in the left ventricular dP/dt_max after docarpamine and levodopa were 36.6±14.2 and 39.2±12.1%, respectively. The two drugs also produced similar decreases in renal vascular resistance (21.2±2.2 and 13.6±3.4%, respectively) and increases in renal blood flow (27.9±3.2 and 17.9±5.2%, respectively), however, the duration of renal vasodilation after docarpamine was longer than that of levodopa. Oral administration of the two drugs in conscious dogs produced vomiting. The ED₅₀ value of the emetic effect for docarpamine was greater than 160 mg/kg, and that for levodopa was 11.0 mg/kg. The emesis was inhibited by pretreatment with a DA₂ antagonist, domperidone. In conclusion, docarpamine and levodopa produced similar cardiorenal effects, but the emetic effect of docarpamine was much weaker than that of levodopa. Docarpamine can be used as a selective dopamine prodrug for the peripheral circulation.

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Helodermin (HDM) belongs to the vasoactive intestinal polypeptide (VIP) family of polypeptides. Degradation of HDM in the tracheal tissue isolated from a guinea-pig and by an isolated enkephalinase was studied and compared with the degradation of VIP. The tracheal relaxing activity of VIP was potentiated by enkephalinase inhibitors, thiorphan and phosphoramidon, while the activity of HDM was not potentiated. On the other hand, bestatin, an aminopeptidase inhibitor, and captopril, an angiotensin converting enzyme inhibitor, did not influence the activity of VIP and HDM. The data suggests that the degradation of VIP but not HDM in the trachea was done by enkephalinase. Enkephalinase was then purified from the lung and the striatum membrane fraction through a DEAE-cellulose column, chromatofocusing column and hydroxyapatite column. The purified enkephalinase from the lung hydrolyzed VIP but not HDM. HDM and VIP were, however, hydrolyzed by the striatum enkephalinase. There was only a partial degradation of HDM by the striatum enkephalinase and the hydrolysis rate of HDM was slower than that of VIP. The degradation of VIP and HDM was inhibited by thiorphan. In conclusion, we found that VIP but not HDM was degraded by enkephalinase present in the respiratory system such as the trachea and the lung. Furthermore, enkephalinase, which hydrolyses HDM, was present in the brain.

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Effect of carrageenan-induced inflammation on hepatic drug metabolism was studied in male and female Wistar rats. One day after treatment of male and female Wistar rats with carrageenan (1%, 0.1 ml, s.c.) (i) a prolongation of the duration of sleeping time induced by hexobarbital (100 mg/kg, i.p.), (ii) decreases biotransformation of hexobarbital, aminopyrine and ethylmorphine in the hepatic 9000×g supernatants (S-9) and (iii) a decrease in cytochrome P-450 content were observed in males but not female rats. However, carrageenan treatment did not alter aniline hydroxylase activity in animals of either sex. Carrageenan also suppressed induction of hexobarbital, aminopyrine and ethylmorphine metabolism by phenobarbital treatment, and depressed the induction of hepatic S-9 cytochrome P-450 content caused by phenobarbital treatment. These data show that there is a sex-related difference in the ability of carrageenan to alter hepatic drug metabolism, which is substrate-specific, in the rats.

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The sodium salts of the 3, 5-dichloro, 3, 5-dibromo-, 3, 5-diiodo-, and 5-methoxy-analogs of salicylic acid have been evaluated as enhancers of rectal insulin absorption. A relationship was found between adjuvant potency and relative lipophilicity. Maximal adjuvant activity was obtained with 0.1 M 3, 5-dichlorosalicylate. Higher concentrations (0.15 M) of 3, 5-diiodosalicylate produced a decline in adjuvant activity, which may be associated with extraction of specific cellular proteins. This may indicate the existence of an optimal salicylate lipophilicity for adjuvant efficacy. Relative adjuvant activity was found to be related to the lymph : plasma absorption ratio of [¹²⁵I] insulin. Lymphatic uptake of insulin was not related to lymph flow rate.

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The bioavailability in beagle dogs and the dissolution rates of cyclandelate from five capsule preparations commercially available in Japan were measured. One of the capsules that showed an extremely low bioavailability in humans also showed the lowest bioavailability in beagle dogs, although the difference in bioavailability with the highest preparation was smaller than in humans. A significant correlation was obtained between the results of the studies in humans and beagles. However, the power of the test using beagles was extremely low in comparison with that in the human study. Food enhanced the bioavailability of cyclandelate from the capsules having the highest and lowest bioavailability in the fasted state in beagles as observed in the human study previously. The bioinequivalence of the cyclandelate capsules detected in the fasted state disappeared in the fed state in the beagle dog study, while the bioinequivalence still remained in the non-fasted state in human subjects. Thus bioequivalence testing in the fed state led to different results in both species. The most poorly bioavailable capsule in both species in the fasted state showed a slow dissolution rate by several dissolution methods with moderate stirring. In order to obtain a good correlation with in vivo bioavailability, a large volume of test solution and addition of Tween 80 were required. Extensive growth of whiskers (needle-like crystals) was observed in the entire capsule mass having the lowest bioavailability.

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The metabolism of strychnine was studied using liver microsomes of rats treated with phenobarbital or 3-methylcholanthrene (MC). The phenobarbital-treatment resulted in 7.9-fold and 4.8-fold increases in 2-hydroxylation and N-oxidation of strychnine, respectively. The formation of 16-hydroxystrychnine, strychnine 21, 22-epoxide and 22-hydroxystrychnine was induced about 2-fold. MC-treatment resulted in only 1.4-fold induction of each oxidation activity. In addition, strychnine 2-hydroxylation activity was markedly induced in liver microsomes of phenobarbital-treated mice, guinea pigs, rabbits and dogs (2.5-10.5-fold). Induction of N-oxidation activity was also higher than that of the three other oxidation activities. A reconstituted system of strychnine metabolism using cytochrome P-450 isozymes, P-450I (P450IIB1) and P-450II (P450IIB2), purified from liver microsomes of phenobarbital-treated rats showed significantly high and selective activities towards 2-hydroxylation and N-oxidation of strychnine. This characteristic metabolism of strychnine appears to occur in common with interspecies P450IIB gene subfamily. The pH Optima of 2-hydroxylation and N-oxidation of strychnine were between 8.4 and 8.6 in the microsomes of phenobarbital-treated rats, while that of N-demethylation of benzphetamine, a typical substrate of phenobarbital-inducible cytochrome P-450, was between 7.4 and 7.6. In a reconstituted system with P-450I, strychnine oxidation was little affected by pH change, while benzphetamine N-demethylation activity was decreased in the alkaline side. Among several oxidations tested, only ethylmorphine N-demethylation underwent the same pH effect as did strychnine oxidation with the microsomes and reconstituted system. These results indicate that the optimum conditions for a P-450 isozyme to interact with the substrates may not necessarily be the same.

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We investigated the environmental differences of a pyridine derivative-access sites between hog gastric (H⁺, K⁺)-ATPase and dog kidney (Na⁺, K⁺)-ATPase. The environmental differences are inferred from the marked contrasts in inhibition properties of (Z)-5-methyl-2-[2-(1-naphthyl) ethenyl]-4-piperidinopyridine hydrochloride (AU-1421) between the two adenosine triphosphatases (ATPases). AU-1421 is a hydrophobic pyridine derivative which inhibits (H⁺, K⁺)-ATPase and (Na⁺, K⁺)-ATPase competitively with respect to K⁺. AU-1421 inhibition of (Na⁺, K⁺)-ATPase activity is preincubation time-dependent, pH-independent (pH 6.4-8.4), and hardly reversible by dialysis. These features are opposite to those found with the gastric (H⁺, K⁺)-ATPase. Furthermore, in the presence of dilute sodium dodecyl sulfate (30-120 μM), the inhibitory potency of AU-1421 for (Na⁺, K⁺)-ATPase is increased, whereas the inhibitory potency for (H⁺, K⁺)-ATPase is decreased. These results favor proposals that protonated species of AU-1421 interact with its access-site of (H⁺, K⁺)-ATPase at the exterior surface of the enzyme molecule by ionic interaction, whereas AU-1421 interacts with its access-site of (Na⁺, K⁺)-ATPase at the interior domain of the enzyme molecule predominantly by hydrophobic interaction. The differences indicate the existence of a different feature of K⁺-access sites between the two ATPases.

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