We investigated the effect of long-term administration of the angiotensin-converting enzyme inhibitor lisinopril on renal arterioles in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) using a morphometric method and vascular cast technique. Rats were treated with lisinopril beginning at 4 weeks of age. At 15 weeks of age, the kidney vessels were fixed when maximally relaxed. Resin was perfused into the right kidney to make a cast of the renal vasculature. The opposite kidney was used for the morphometric study to evaluate structural changes of the vascular wall. The vascular cast study demonstrated a significant reduction in the lumen diameter of the afferent but not the efferent arterioles in SHR compared with those in WKY. In lisinopril-treated rats, the afferent arteriolar lumen diameters were significantly larger than those of the respective control groups in both strains. However, treatment did not affect the lumen diameter of efferent arterioles in either strain. The morphometric study revealed that the cross-sectional area of afferent arteriolar media was significantly smaller in SHR than WKY, suggesting that the impaired growth of the afferent arteriolar media was involved in the narrowed afferent arteriolar lumen in SHR. The presence of significantly smaller media-lumen ratio, greater media cross-sectional area, and larger internal as well as external diameters of the afferent arterioles in treated SHR than in untreated rats suggested that lisinopril treatment normalizes the structure of the afferent arterioles in SHR by vascular reverse remodeling and by inducing media growth.
To separately assess intestinal and hepatic first-pass effects with absorption ratio data, we have established an experimental model of rats double-cannulated into the portal and jugular veins. The model allows us to take blood samples simultaneously from conscious rats that have recovered from surgical damage. Double cannulation did not alter the physiological and hematological conditions. Moreover, the plasma concentration profiles of unchanged drug following oral and intravenous administration in the double-cannulated rats were not different from those of rats single-cannulated into the jugular vein. These results suggest that the model can be useful for separately assessing intestinal and hepatic first-pass effects. We evaluated the first-pass effects in the intestine and the liver separately using this model. S-1452, as a model drug with 94% absorption ratio, was administered intravenously and orally to the double-cannulated rats, and the drug concentrations in the portal and systemic plasma were determined, and the rates of elimination from the intestine and liver were estimated. In the first pass, approximately 26% and 56% of the dose were extracted by the intestine and liver, respectively. This method, in which the animal is not restricted nor under anesthesia, allows us to obtain reliable values of individual first pass effects in the intestine and liver. This method can also be an effective tool for assessing the site and extent of drug-drug interaction on the first-pass effects.
The cellular localization of endothelin receptors in the inner medulla of the rat kidney was investigated by using high resolution light and electron microscopic autoradiography, with the microwave irradiation fixation methods. Kidney slices were incubated with 125I-endothelin-1 alone or with selective ligands for the endothelin ETB and/or ETA receptors for light microscopic autoradiography. At the microscopic level, 125I-endothelin-1 was found to bind specifically to the glomeruli, arterioles and peritubular spaces in the cortex and vasa recta and surrounding tissues in the inner medulla. These bindings were also observed when the tissue slices were incubated in the presence of IRL1620 (ETB receptor agonist) or 97-139 (ETA receptor antagonist). Electron microscopic autoradiography using 125I-endothelin-1 in the inner medulla revealed silver grains over endothelial cells of the vasa recta and interstitial and collecting duct cells. No grains were detected over inner lining cells of the thin limbs of Henle's loop. These interstitial cells contained abundant microorganelles and lipid droplets, and had extensive cytoplasmic processes that closely related to the basement membranes of the vasa recta and loop of Henle. These findings demonstrate that type 1 interstitial cells are also primary sites for endothelin receptors as well as endothelial cells of the vasa recta and collecting duct cells in the inner medulla.
S-1108, the prodrug of S-1006, was given to healthy volunteers three times a day (TID) for 8 days in a dose of 200 mg in a crossover placebo-controlled study. The safety of S-1108 and the pharmacokinetics of S-1006 and pivalic acid liberated from pivaloyloxymethyl ester of S-1108 were investigated. There were no abnormal symptoms or signs, as observed by physical and laboratory tests. The half-life and area under the concentration-time curve of S-1006 was reduced from 1.11 ± 0.17 h at the first dose to 0.87 + 0.18 h at the last dose and from 7.30 ± 1.10 to 5.20 ± 0.85 ,ug. h/ml, respectively. However, there was no significant difference in the peak concentration between the two doses. Pivalic acid was found to be completely detoxified by conijugation with carnitine. The total urinary recovery of pivalic acid as pivaloylcarnitine was 98.7 ± 3.6%, resulting in an increase of daily carnitine urinary excretion two-to threefold the predose value. During the multiple administration of S-1108, the plasma carnitine concentration was reduced to and maintained at 50 to 70%o of the control value, suggesting that there might be enough carnitine store in the body to detoxify the pivalic acid in a dose of 200 mg TID. Moreover, the reduced plasma carnitine was rapidly returned to the control value within a few days after the cessation of the administration of 200 mg TID.S-1108 is a new oral cephem antibiotic that possesses a pivaloyloxymethyl ester group. It is easily deesterified in the intestine and converted to its active form, S-1006, which is highly active against a wide range of gram-positive and gram-negative bacteria except several bacteria such as Pseudomonas aeruginosa and enterococci. There are some other antibiotics that are esterified with a pivaloyloxymethyl group to increase the extent of absorption. These prodrugs, such as cefteram pivoxil, pivampicillin, and pivmecillinam, have already been used for the treatment of infectious diseases. The clinical efficacy, safety, and pharmacokinetics of these active forms were sufficiently investigated.Recently, it has been reported that prodrugs having a pivaloxyloxymethyl ester group might promote myopathic carnitine deficiency in humans (4). However, the pharmacological, toxicological, and pharmacokinetic properties of metabolites liberated from these prodrugs have not been sufficiently investigated. It is well known (2, 9) that a prodrug having a pivaloyloxymethyl ester group is further metabolized to produce pivalic acid and formaldehyde. Pivalic acid is excreted in urine mainly as a conjugate with carnitine, resulting in a decrease of carnitine stores in the body, especially in the case of long-term therapy with these prodrugs (4-6, 11). The metabolism of S-1108 was studied, as shown in Fig. 1 (10a). As, mentioned above, the liberated pivalic acid from S-1108 might reduce carnitine stores by the form'ation of pivaloylcarnitine. The purpose of this study is to investigate the safety of S-1108 and the pharmacokinetics of S-1006 and pivalic acid liberated in healthy vol...
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