Influence of Chronic Renal Failure on Stereoselective Metoprolol Metabolism in Hypertensive Patients

Abstract

The influence of chronic renal failure on the stereoselective metabolism of rac-metoprolol was investigated in 15 hypertensive patients, 7 of them with chronic renal failure and 8 with normal renal function. They were treated with rac-metoprolol (200 mg) for 7 days. The patients of both groups presented stereoselectivity in metoprolol metabolism, favoring the formation of 1'R-alpha-hydroxymetoprolol (AUC(1(')R/1(')S)(0-24) approximately 2.5) and (R)-metoprolol acidic metabolite (AUC((S)/(R))(0-24) = 0.8), the latter resulting in the plasma accumulation of (S)-metoprolol (AUC((S)/(R))(0-24) = 1.2). Patients with chronic renal failure presented plasma accumulation of the 4 alpha-hydroxymetoprolol isomers and of both metoprolol acidic metabolite enantiomers. A 50% reduction in Cl(R) does not explain the 3- to 4-fold plasma accumulation of metoprolol acidic metabolite in this group, suggesting that other pathways of metoprolol elimination are affected in chronic renal failure in addition to renal excretion. Chronic renal failure does not change the stereoselective kinetic disposition of metoprolol but modifies its stereoselective metabolism, inducing some of the CYP enzymes involved in the formation of the metoprolol acid metabolite.

Influence of gestational diabetes on the stereoselective pharmacokinetics and placental distribution of metoprolol and its metabolites in parturients

“…AUC 1′R : 1′S ratios of 2.84 for the present hypertensive parturients agree with the values reported by Cerqueira et al . in a study of hypertensive patients (AUC 1′R : 1′S = 2.87) and with the values reported by Boralli in a study of healthy volunteers (AUC 1′R : 1′S = 3.07).…”

“…The CL/ F values of both metoprolol enantiomers obtained for the parturients investigated were higher than those reported by Cerqueira et al . in a study of hypertensive patients (men and non‐pregnant women) (1.26 vs. 1.53 l h −1 kg −1 ) and by Boralli in a study of non‐pregnant healthy volunteers (1.66 vs. 2.31 l h −1 kg −1 ). AUC(0,∞) S‐(−) : R‐(+) enantiomeric ratios of 1.39 were previously reported by Johnson & Burlew who investigated non‐pregnant healthy volunteers treated with a single dose of racemic metoprolol.…”

“…Metoprolol is mainly eliminated as inactive O‐desmethylmetoproloic acid (AODM – 65% of the dose) and as active α‐hydroxymetoprolol (OHM) (10% of the dose) . CYP2D6 and CYP3A, in addition to other CYP isoforms, participate in the O‐demethylation of metoprolol . The oxidative metabolism of metoprolol represents 85% of its elimination, CYP2D6 being responsible for approximately 70% of this metabolism, whereas a small proportion is dependent on CYP3A4 activity .…”

“…CYP2D6 and CYP3A, in addition to other CYP isoforms, participate in the O‐demethylation of metoprolol . The oxidative metabolism of metoprolol represents 85% of its elimination, CYP2D6 being responsible for approximately 70% of this metabolism, whereas a small proportion is dependent on CYP3A4 activity . The formation of α‐hydroxymetoprolol depends on the genetically determined activity of CYP2D6 .…”

An evaluation of the CYP2D6 and CYP3A4 inhibition potential of metoprolol metabolites and their contribution to drug–drug and drug–herb interaction by LC‐ESI/MS/MS

“…ODM is further metabolized to form MET acid. Recent studies suggest the involvement of CYP3A isozymes in the O-demethylation pathway in rats (Boralli et al, 2009) and humans (Cerqueira et al, 2005). Multiple dose administration of MET showed increased plasma concentration of MET when compared with single-dose treatment (Kendall et al, 1980).…”