Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics

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An insertion/deletion polymorphism of the angiotensin converting enzyme (ACE) gene has been reported to affect the activity of ACE. This study was conducted to investigate the relationship between the action of the angiotensin II receptor antagonist CS-866 and the insertion/deletion (I/D) polymorphism of the ACE gene in Japanese healthy subjects.
The effects of a single oral dose of CS-866 16 mg on blood pressure (BP) and pulse rate in relation to the ACE genotype were studied in 12 healthy men, 7 with the II genotype and 5 with the DD genotype. The pharmacodynamics of CS-866 in relation to the ACE genotype was evaluated. The effect of CS-866 on the plasma renin-angiotensin system was determined.
The plasma levels of angiotensin II were significantly higher in the DD genotype than the II genotype before the administration of CS-866. The insertion/deletion polymorphism did not change any pharmacokinetic parameters of CS-866 in plasma.
BP in the supine position decreased with the administration of CS-866, while the pulse rate increased. The increase in plasma levels of angiotensin II following administration of CS-866 was associated with the potency of the action of CS-866. The BP-lowering action of CS-866 was greater in the DD genotype subjects than in II genotype subjects. Postural change amplified this genetic difference.
The increase in the levels of angiotensin II following administration of CS-866 appears to be closely related to the antihypertensive action of CS-866. Higher activity of ACE in the subjects with the DD genotype might potentiate the action of CS-866, probably intensifying the rise in the levels of angiotensin II.

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The purpose of this study was to evaluate the distribution of CPT-11 and its active metabolite, SN-38, in pleural and pericardial fluid after intravenous administration.
Two patients with lung cancer were treated with intravenous CPT-11 (60 mg/m²) on days 1, 8, and 15. The CPT-11 was detected in the pleural fluid 1.5 hr after the begining of intravenous infusion, and the level reached the maximum 24 hrs later. Similarly, the active metabolite SN-38 was detected in the pleural fluid 1.5 hr after the begining of intravenous infusion, and SN-38 concentration in the pleural fluid was almost as high as that in plasma 24 hrs later. These results suggest that intravenously administered CPT-11 may penetrate the thoracic cavity and may be metabolized to SN-38 there. The proportions of maximum concentrations of CPT-11 and SN-38 in the pleural fluid to the corresponding plasma levels were 20.4% and 28.5%, respectively. In addition, the AUCs of the lactone form SN-38 were much lower than those of the carboxyl form in the pleural fluid.
CPT-11, SN-38 and SN-38 glucronide showed similar pharmacokinetics in the pericardium as that in plasma.

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