The aim of our study was to determine the neuropharmacokinetics of S18986, a positive allosteric modulator of AMPA-type receptors, in the rat. We focused on its blood-brain barrier (BBB) uptake and on its brain intra- and extra-cellular fluid (bICF-bECF) partitioning. The BBB transport was measured using the in situ brain perfusion technique. bECF concentrations were determined by microdialysis in the frontal cortex (FC) and dorsal hippocampus (DH), and blood samples were collected simultaneously through a femoral catheter. Cerebrospinal fluid and brain tissue concentrations were determined using a conventional pharmacokinetic approach. Using all the experimental data, pharmacokinetic modeling was applied to describe the S18986 blood-brain disposition. The brain uptake clearance of S18986 was found to be high (20 μl s−1 g−1). Terminal half-lives were similar in plasma and brain (1 hour). Experimental and predicted blood and brain concentrations were a good fit with the pharmacokinetic model, which assumed first-order rate constants at each interface. Ratios of bECF to the unbound plasma area under the curve (AUC) were 0.24 in FC and 0.25 in DH, whereas ratios of bICF/plasma AUC were 1 in FC and 1.5 in DH. We conclude that despite the ratio of bECF/plasma AUC is below 1, there is nevertheless an elevated BBB uptake of S18986. This can be explained by its nonhomogenous bECF/bICF partitioning, since S18986 mainly distributes into hippocampal bICF. This illustrates the importance of taking bECF/bICF partitioning into account when interpreting the neuropharmacokinetics of a drug.
1 Perindopril is a prodrug which is hydrolysed in vivo to the active metabolite perindoprilat, an angiotensin‐converting enzyme inhibitor. Perindoprilat glucuronide is also found in plasma. 2 The pharmacokinetics of perindopril and its metabolites were studied after administration of a single 4 mg dose to hypertensive patients with various degrees of renal failure. 3 The absorption and elimination of perindopril were not influenced by the degree of renal failure. 4 The mean area under the serum concentration‐time curve of the active metabolite perindoprilat increased from 93 ng ml‐1 h in subjects with normal renal function to 1106 ng ml‐1 in patients with severe renal failure, whereas its half‐life varied from 5.0 to 27.4 h. 5 In the same subjects, the mean area under the curve of perindoprilat glucuronide increased from 78 to 513 ng ml‐1 h, while its half‐life varied from 1.8 h to 7.7 h. 6 Perindopril, perindoprilat, and perindoprilat glucuronide were dialysable. 7 The extent and duration of serum angiotensin‐ converting enzyme inhibition was augmented in renal failure. The mean area under the inhibition time curve (extrapolated to infinity) increased from 2490%.h in subjects with normal renal function to 42241 %.h in patients with severe renal impairment. The half‐life of inhibition varied from 12.1 h to 100.4 h. This effect of renal failure on the pharmacodynamics of perindoprilat was more pronounced than its influence on perindoprilat kinetics. 8 In view of the important influence of renal impairment on the elimination and action of the active substance perindoprilat, a dosage reduction of perindopril is proposed in in patients with renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)
Summary: The aim of this article is to review the pharmacokinetics of perindopril and its active metaholite perindoprilat in high-risk populations in comparison with their basic features in healthy volunteers. As it has been shown that the kinetics of perindoprilat are mainly affected by renal insufficiency, a dosage reduction is therefore recommended on initiation of treatment in elderly patients and in those with renal failure according to the degree of renal failure. In patients with chronic heart failure, the kinetics of both perindopril and perindoprilat were shown to have been altered, also indicating the need for an initial dosage reduction in such patients. Hepatic impairment had no significant effect on the kinetics of either the prodrug or the active metaholite.
Abstract1. Adult rat hepatocytes co-cultured with rat liver epithelial cells were used to evaluate chronic cytotoxicity of a new α2 agonist, oxaminozoline (S-3341-3) compared to that of clonidine. The same maximum non-toxic concentration (25 μg per ml of medium) was found for both drugs after a daily treatment for 12 days.2. Oxaminozoline metabolism was analysed in short-term hepatocyte cultures. Four metabolites resulting from oxidation or hydrolysis of the parent drug were identified. Three of the metabolites were identical to those reported in vivo. The presence of an additional minor metabolite in culture may be due to the higher metabolic rate of the drug in this model system.
1. Perindopril, an orally active angiotensin converting enzyme inhibitor, was given to 23 hypertensive patients with stable chronic renal failure for 15 days. The dose of perindopril was 2 or 4 mg once a day according to the degree of renal failure. The creatinine clearance of the patients ranged from 6 to 67 ml min‐1 1.73 m‐2. The pharmacokinetics of perindopril and perindoprilat, its active metabolite, were studied after acute and chronic administration of perindopril. 2. The drug was well tolerated and creatinine clearance was unaltered by treatment. 3. In both groups, steady‐state was reached within 3 days of chronic treatment. 4. After both acute and chronic drug administration renal impairment had no effect on perindopril pharmacokinetics but the pharmacokinetics of perindoprilat were altered significantly. After chronic administration the serum accumulation ratio was 1.81 in patients with mild renal failure and 5.35 in patients with severe renal failure. Chronic administration did not modify the renal clearance of perindoprilat nor its elimination half‐life. 5. A significant correlation between the renal clearance of perindoprilat and creatinine clearance was observed (r = 0.87 first dose, r = 0.83 last chronic dose). 6. A non‐linear relationship between serum perindoprilat concentration and inhibition of angiotensin converting enzyme was described by a modified Hill equation. Values of IC50 were 1.11 +/‐ 0.07 micrograms I‐1 (mean +/‐ s.d.) in patients with severe renal failure and 1.81 +/‐ 0.20 micrograms l‐1 in patients with moderate renal failure. Chronic administration increased maximal inhibition and decreased the time to maximal inhibition only in patients with severe renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)
The aim of this article is to review the pharmacokinetics of perindopril and its active metabolite perindoprilat in high-risk populations in comparison with their basic features in healthy volunteers. As it has been shown that the kinetics of perindoprilat are mainly affected by renal insufficiency, a dosage reduction is therefore recommended on initiation of treatment in elderly patients and in those with renal failure according to the degree of renal failure. In patients with chronic heart failure, the kinetics of both perindopril and perindoprilat were shown to have been altered, also indicating the need for an initial dosage reduction in such patients. Hepatic impairment had no significant effect on the kinetics of either the prodrug or the active metabolite.
