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COMPARISON OF PLASMA LEVELS AND EXCRETORY ROUTES BETWEEN NO.189 AND NO.407, POTENT THROMBIN INHIBITORS

English (英語)

The Kobe journal of the medical sciences

26(1)

11-31

1980-03

Two potent thrombin inhibitors, No. 189 and No. 407, have equivalent activities in vitro. However, No. 407 offered a greater margin of safety in toxicity test as compared with No. 189. In general, the pharmacokinetic characteristics of a drug, especially plasma levels and distribution, are responsible for the toxicity and moreover for the principal therapeutic efficacy. For the purpose of estimating the difference in pharmacological activity between No. 189 and No. 407, plasma levels after various routes of administration (intravenous injection (i.v.), continuous intravenous infusion (constant infusion), subcutaneous injection (s.c.) and oral administration (p.o.)) were investigated. The administration of No. 407 to rabbits resulted in high and sustained plasma levels exceeding markedly that of No. 189. The relative bioavailability was estimated by comparing the Areas Under the plasma concentration - time Curves (AUC). The% ratio of AUC of No. 407 to No. 189 was 4.9 by i.v., 8.5 by s.c. and 72.5 by p.o. The ratio of AUC of p.o. to i.v. was 3.4% in No. 407 and 0.23% in No. 189. In the experiments of constant infusion of No.407, lower plasma levels were obtained by the infusion into the hepatic portal vein as compared with those by the infusion into the femoral vein. Subsequently, in order to clarify the difference in the plasma concentrations between No. 189 and No. 407, in situ intestinal absorption, excretion and binding to liver homogenate were investigated. In absorption experiments, no significant difference was observed between No. 189 and No. 407. The values of percent absorbed in 1 hour were 8.7% with No. 189 and 12.5% with No. 407. These two inhibitors would be ranked among poorly absorbable compounds. In excretion experiments, 52.5% of No. 189 and 67.0% of No. 407 were excreted within 3 hours after constant infusion in rabbits. In that case, the renal recovery was 7.5% in No. 189 and 32.5% in No. 407. In binding experiments, 50-60% of No. 189 was bound to liver homogenate (mainly composed of the membrane and nuclei fraction of liver) but only 10% was bound in case of No.407. From the results of these experiments, it is suggested that hepatic first-pass uptake and biliary excretion were the most important factors by which the anti-thrombin activity of these inhibitors in plasma was mainly determined. In addition, the marked difference in the distribution volume seems to be one of the factors by which toxicity of a drug is influenced. Furthermore, species difference as to plasma levels and excretory routes was examined using No. 407. Lesser plasma levels were obtained by the administration to beagle dogs than to rabbits after i.v. and p.o. Especially by p.o., these differences were markedly great. Excretion in the rabbits was predominantly renal (67% total recovery) whereas in the dogs predominant biliary excretion (59% of total recovery) was observed.

plasma level

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