Biomedical subjects
R B Cubela
Publications and source records attributed to R B Cubela.
Lisinopril pharmacokinetics in chronic renal failure.
1. Lisinopril, a new orally active angiotensin converting enzyme inhibitor, was given to eight patients with stable chronic renal failure, in a dose of 5 mg 24 h-1 for 1 week. Creatinine clearance of the subjects ranged from 0.22 to 1.11 ml s-1. Lisinopril pharmacokinetics were studied over 8 days. 2. There was a close correlation between creatinine clearance and total 'area under the curve' over the 8 days of study (r = -0.88, P less than 0.05), and plateau lisinopril concentration and creatinine clearance (r = -0.77, P less than 0.05). 3. Serum angiotensin converting enzyme activity was inhibited in proportion to log serum lisinopril concentration (r = -0.99, P less than 0.001). Calculated IC50 was 47 ng lisinopril ml-1. from pooled data, with individual patients IC50 ranging from 20 to 70 ng lisinopril ml-1. 4. Creatinine clearance was unaltered by treatment. Serum potassium rose to over 5 mmol 1-1 in four patients, without adverse clinical effect.
Characterization of angiotensin converting enzyme (ACE) in the testis and assessment of the in vivo effects of the ACE inhibitor perindopril.
Angiotensin converting enzyme (ACE) was characterized by radioligand studies utilizing the potent ACE inhibitor 351A, a derivative of lisinopril. Ligand binding characteristics were similar for ACE derived from testis, lung, and kidney, despite known differences in structure between ACe from these sources. This observation suggests that the ACE active enzymatic site is similar in different tissues. The effect of the orally active ACE inhibitor perindopril was studied ex vivo in tissues of the rat after oral gavage. Radioligand bound to tissue ACE was reduced after perindopril treatment, in tissue homogenates of lung and kidney, but not testis. Autoradiographs of radioligand binding to tissue sections obtained ex vivo after oral perindopril showed inhibition of ACE in the aorta, lung, and kidney, but did not reveal any inhibition of ACE in the testis. ACE in small vessels of the testis was inhibited as in the aorta, while at the same time testicular ACE was unaffected. ACE in rat testis appears to have a similar enzymatic binding site to ACE from the lung and kidney. Perindopril inhibited ACE in the lung and kidney but did not affect ACE in the testis, suggesting the drug is limited in testicular penetration by the blood-testis barrier. This may explain the lack of any reports of adverse effects of ACE inhibitors on testicular function.
Inhibition of tissue angiotensin converting enzyme by perindopril: in vivo assessment in the rat using radioinhibitor binding displacement.
Changes in angiotensin converting enzyme (ACE) derived from plasma, lung, aorta, brain, kidney and testis were measured in rats treated with perindopril. Angiotensin converting enzyme was measured by a radio inhibitor binding method using 125I351A. Rats were gavage fed perindopril (1, 4 and 8 mg/kg) and changes followed over 48 hr. Plasma and kidney ACE were both affected acutely with reduction of 125I351A binding to less than 5% of that in control animals 1 and 2 hr after gavage. Ligand binding to ACE in plasma and kidney returned to control levels after 24 hr. Ligand binding to ACE in lung, aorta and brain also was displaced after perindopril treatment. Changes were of a lesser degree than in plasma or kidney. Maximal effect was 1 to 4 hr after treatment and persisted through 24 hr postgavage. Ligand binding to ACE from testis was little altered over the time period of study. In a dose varying study rats were gavage fed perindopril (0-32 mg/kg) and tissues were studied 4 hr later. Ligand binding to plasma and kidney ACE was displaced by 50% at a dose of 1 mg/kg or less, whereas a dose of 16 to 32 mg/kg was required for a similar effect on ACE in lung, aorta and brain. ACE in testis was only affected to a small degree at a dose of 32 mg/kg. ACE is tissues was inhibited differentially after oral treatment with perindopril. Although differing in bioavailability, bioactivation of the drug or different binding properties of the enzyme could all account for the results, the most likely explanation is that there is variation in tissue penetration of the drug.
Inhibition of angiotensin converting enzyme (ACE) in plasma and tissues: studies ex vivo after administration of ACE inhibitors.
Two methods of radio-inhibitor binding to tissue membrane homogenates and in vitro autoradiography have been used for ex vivo studies on the inhibition of tissue angiotensin converting enzyme (ACE) following acute and chronic administration of ACE inhibitors. Tissue ACE is differentially inhibited in time and degree in different tissues of the rat. Plasma and kidney ACE are inhibited completely at low doses whereas lung and aorta are only inhibited by 60-70%, even after very high does of ACE inhibitors. In the brain only those structures outside the blood-brain barrier are inhibited at low doses but at high doses perindopril appears able to cross the blood-brain barrier. Similarly, testicular ACE is not inhibited and appears to be protected by a blood-testis barrier. Preliminary results suggest that after chronic administration there is also a variable pattern of induction and inhibition of ACE in different tissues. By relating the degree of tissue inhibition to physiological responses it may be possible to determine the role of local renin-angiotensin systems in regional haemodynamics and in the hypotensive action of ACE inhibitors. Further, the techniques of radioligand inhibitor binding and in vitro autoradiography can be extended to other important cardiovascular enzymes (renin and kallikrein) when suitable high affinity specific inhibitors become available.
Effects of perindopril on angiotensin converting enzyme in tissues of the rat.
Perindopril, an orally active angiotensin converting enzyme (ACE) inhibitor, was fed by gavage to male Sprague-Dawley rats. The effect on tissue ACE was measured ex vivo by quantitation of binding of the specific radioligand 125I-3511A to ACE in tissue homogenates. In an acute time-course study perindopril (1, 4 or 8 mg/kg) inhibited plasma ACE activity by more than 90% in 1 h but no inhibition remained after 24 h. Kidney ACE was affected to a similar degree and followed a similar time-course of inhibition to plasma ACE. In contrast, ACE was inhibited to a lesser degree in lung and aorta homogenates, with maximum effect 4-8 h postgavage, and with inhibition persisting 48 h following the dose. In testis homogenates, ACE remained unaltered following the administration of perindopril at all three doses. Therefore we conclude that plasma ACE inhibition does not parallel tissue effects, and that drug penetration into the testis appears to be limited.