Influence of chronic renal failure on captopril pharmacokinetics and clinical and biological effects in hypertensive patients.

Abstract

The pharmacokinetic parameters of unchanged plasma captopril and the kinetics of the drug effects on plasma converting enzyme activity (PCEA), plasma renin activity (PRA), plasma aldosterone (PA) and mean blood pressure (MBP) were studied over 24 h after oral administration in three groups of hypertensive patients: with normal renal function (group 1, plasma creatinine less than 110 mumol/l, n = 10), with moderate chronic renal failure (group 2, 135 less than plasma creatinine less than 450 mumol/l, n = 10) and with severe chronic renal failure (group 3, plasma creatinine greater than 500 mumol/l, n = 10). Renal impairment had no effect on plasma captopril Cmax, CLtot and relative bioavailability (AUC). In contrast, captopril kel decreased while T1/2 increased progressively from group 1 to group 3. PCEA blockade (T1/2 and AUC) was increased significantly and proportionally to the degree of renal impairment. However, there were no differences between the three groups regarding captopril‐induced modifications of PRA and PA. Although the maximal reduction in MBP was identical in the three groups, the overall antihypertensive effect (AUC) of captopril increased significantly and progressively from group 1 to group 3, especially in duration. There was no correlation between basal plasma creatinine values and unchanged captopril relative bioavailability (AUC) and between unchanged captopril relative bioavailability (AUC) and the drug effects (AUC) on PCEA, PRA, PA and MBP. However there was a correlation between basal plasma creatinine values and plasma captopril T1/2, PCEA blockade (AUC) and overall antihypertensive effect (AUC). The apparent discrepancy between the lack of effects of chronic renal failure on plasma unchanged captopril bioavailability and its potentiating effects on PCEA blockade and MBP reduction may be accounted for by the renal impairment‐induced accumulation of captopril metabolites.

Pharmacokinetics and biological effects of captopril and hydrochlorothiazide after acute and chronic administration either alone or in combination in hypertensive patients.

“…It appears from these results (a) that acute administration of the three treatments resulted in an increase in PRA ( Figure Sa), and (b) that, starting from higher basal values, this increase in PRA also developed after chronic administration ( Figure Sb). However, while HCTZ-induced increase in PRA was similar on days 1 and 45 ( Figure Se It appears from our data that the pharmacokinetic parameters calculated (a) for free unchanged captopril and total captopril after acute administration of captopril, and (b) for HCTZ after acute administration of HCTZ (Table 2) are in good agreement with the data from the literature for free unchanged captopril (Jarrott et al, 1982;Richer et al, 1984;Giudicelli et al, 1984), for total captopril (Kripalani et al, 1980;Duchin et al, 1982) and for HCTZ (Beermann & Groschinsky-Grind, 1977. It also appears from our data that the two components of the combination tablet exhibit almost similar halflife values, after acute as well as after chronic administration of captopril alone or HCTZ alone (Table 2).…”

Single dose pharmacokinetics of perindopril and its metabolites in hypertensive patients with various degrees of renal insufficiency.

“…Renal excretion is the major route of elimination of captopril consistent with an increased plasma half-life in patients with renal failure (Duchin et al, 1984). There are also indications that the active metabolites of captopril accumulate in renal failure and cause prolonged duration of plasma ACE inhibition and blood pressure reduction (Giudicelli et al, 1984).…”

Can ACE Inhibitors and Angiotensin Receptor Blockers Be Detrimental in CKD Patients?

“…We submit that this could have explained the failure of this study to demonstrate any renal benefits associated with the withholding of ACEI or ARB before contrast exposure, compared to patients who continued to take the ACEI or ARB throughout the study [113,114]. On this same basis, we would argue that the Canadian study by Komenda et al [108] where the ACEI or ARB was stopped for a longer time interval before coronary angiography was then able to demonstrate improved renal outcomes when compared to historical controls in whom concurrent ACEI/ARB therapy was continued uninterrupted through coronary angiography [113,114]. …”