Comparative evaluation of the effects of isradipine and diltiazem on antipyrine and indocyanine green clearances in elderly volunteers

Abstract

Calcium antagonists have been shown to depress hepatic enzymes and accelerate hepatic blood flow. This study was designed to compare the effects of two calcium antagonists, isradipine and diltiazem, on antipyrine and indocyanine green (ICG) clearances in the elderly. Eighteen elderly subjects (aged 65 to 80 years) received either isradipine (5 mg every 12 hours), diltiazem (90 mg every 8 hours), or placebo (every 12 hours) for 4 days. On the third day after the study treatment, a 0.5 mg/kg dose of ICG was administered. Blood samples were obtained over 20 minutes for HPLC determination of ICG plasma concentrations. Ten minutes later, subjects ingested 1.2 gm antipyrine. Blood samples were obtained over 48 hours for HPLC determination of antipyrine plasma concentrations. Mean +/- SD antipyrine clearance after diltiazem (0.0258 +/- 0.0065 L/hr/kg) was significantly lower than that observed after isradipine (0.0334 +/- 0.0098 L/hr/kg) or placebo (0.0329 +/- 0.0082 L/hr/kg). Antipyrine clearance after isradipine was not significantly different from that after placebo. Mean +/- SD ICG clearances after diltiazem (9.17 +/- 1.35 ml/min/kg) or isradipine (9.57 +/- 1.82 ml/min/kg) were significantly higher than that observed after placebo (8.06 +/- 1.45 ml/min/kg). These findings suggest that diltiazem, but not isradipine, affects hepatic enzyme activity in the elderly. Both agents accelerate ICG clearance, a marker of hepatic blood flow.

Mibefradil but not isradipine substantially elevates the plasma concentrations of the CYP3A4 substrate triazolam*1

“…Thus, in contrast to the concentrations of verapamil and diltiazem or their inhibitory metabolites, the concentrations of isradipine in drug‐metabolizing tissues are probably lower than its competitive inhibition constant for CYP3A4 10 . However, because isradipine increases hepatic blood flow, 22 it may slightly increase the hepatic clearance of triazolam and other drugs with an intermediate to high hepatic extraction. In any event, our results are in good agreement with earlier studies that showed that isradipine had no significant effect on the pharmacokinetics of cyclosporine 23 , 24 and even slightly decreased the AUC for lovastatin 25…”

Pharmacokinetic interaction between diltiazem and nortriptyline

“…The major metabolic pathway of diltiazem in man is demethylation, catalysed by the CYP3A subfamily [3]. A decrease in hepatic blood flow with a subsequent decrease in hepatic clearance is an unlikely explanation for the observed increase of plasma nortriptyline, since diltiazem increased hepatic blood flow in elderly volunteers [8], and since the patient was in a stable clinical condition throughout the hospitalisation. by N-hydroxylation [6] and by N-demethylation [5].…”

“…Nortriptyline is also metabolised by the liver, mainly by 10-hydroxylation catalysed by CYP2D6 [4,5]. Diltiazem is a well known inhibitor of hepatic oxidative metabolism, as demonstrated for antipyrine [8,9], imipramine [10] and cyclosporine [11], a pattern compatible with predominant impairment of isoenzymes of the CYP3A subfamily. Since nortriptyline is a high extraction drug [7], its clearance under most conditions is a function of hepatic blood flow.…”

Diltiazem

“…A single oral 90mg dose of diltiazem has been shown to reverse the normal aging-related decline in peak left ventricular filling rate suggesting that the drug may be useful in the treatment of elderly patients with diastolic dysfunction (Manning et al 1991). Klockowski et al (1990) compared the effects of diltiazem and placebo on hepatic blood flow, measured as a function of indocyanine green clearance, in 18 elderly (65 to 80 years-of-age) volunteers. A single intravenous 0.5 mg/kg dose of indocyanine green was given after 48 hours' treatment with diltiazem 270 mg/day or placebo.…”

“…It appears that substantial accumulation of diltiazem via metabolic pathways does not occur with increasing doses during repeated administration (Lanman et al 1985). Klockowski et al (1990) compared the effects of diltiazem and placebo on oxidative drug metabolism in the liver in 18 elderly (65 to 80 years of age) volunteers (using the clearance rate of antipyrine as a marker) randomised to receive oral diltiazem 90mg every 8 hours, and placebo, in a crossover manner. A single 1.2g oral dose of antipyrine was given 2 hours after 48 hours' treatment with diltiazem or placebo.…”