Protein binding of sotalol enantiomers in young and elderly human and rat serum using ultrafiltration

Abstract

The protein binding of sotalol (STL) enantiomers was evaluated using an ultrafiltration technique with serum from young (32 +/- 2 years, n = 5) and elderly (73 +/- 6 years, n = 5) male and female humans, and young (8 weeks, n = 4) and elderly (60 weeks, n = 3) male Sprague-Dawley rats. Serum samples were collected and immediately frozen at -20 degrees C. Within 1 week, the serum samples were thawed at room temperature, and adjusted to pH 7.4 using 0.05 M phosphate buffer, pH 5.0. Aliquots were spiked with 250 ng mL-1 and 500 ng mL-1 of each STL enantiomer, placed in ultrafiltration sets (Microsep, 30K molecular weight cut-off), capped, equilibrated to 37 degrees C, and centrifuged at 1850g for 1.5 h at 37 degrees C. Aliquots of ultrafiltrate and unspun serum were analysed for STL enantiomer concentration using a stereospecific HPLC assay. In all groups, bound fraction was less than 7% for both STL enantiomers. There were no significant differences in bound fraction between groups, or between enantiomers. Adsorption of STL enantiomers to the ultrafiltration device and membrane, evaporative loss of serum samples during centrifugation, and protein concentration in each ultrafiltrate sample were all negligible. It is concluded that the binding of STL in human and rat serum at therapeutic concentrations and physiological temperature and pH is negligible and non-stereoselective.

Enantioselective liquid chromatographic-electrospray mass spectrometric assay of β-adrenergic blockers: application to a pharmacokinetic study of sotalol in human plasma

“…No significant differences were observed for all pharmacokinetic parameters (Table 3). These findings were in agreement with previous studies [19,20] in which no stereoselectivity was observed in the plasma concentrations of sotalol enantiomers, after single oral doses of rac-STL to healthy volunteers. There was, however, some stereoselectivity noted in another study [21], when repeated doses of rac-STL were administered to patients with supraventricular tachycardia.…”

“…There was, however, some stereoselectivity noted in another study [21], when repeated doses of rac-STL were administered to patients with supraventricular tachycardia. It is well known [22] that ␤-adrenergic blockers bind to both Table 3 Mean albumin and ␣ 1 -acid glycoprotein in plasma, but the binding appears to be non-stereoselective, in the case of sotalol [23]. Moreover, the reported stereoselectivity in the renal clearance of sotalol is relatively low, with (−)/(+) renal clearance ratio being 1.05 [20].…”

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

“…On the other hand, dl-sotalol has very weak hERG inhibitory potential with an IC 50 value of 278 μM (Kirsch et al, 2004), but apparently caused QTc interval prolongation at the free plasma concentration of 4.99 μM in common marmosets. dl-Sotalol also prolonged QTc intervals at a free plasma concentration of 7.2 μM in anesthetized dogs (Schnelle and Garrett, 1973;Tabo et al, 2006) and 5.3 μM in humans (Carr et al, 1995;Kimura et al, 1996). The reason why dl-sotalol shows such weak hERG blockade even though it prolongs QT interval via the I K blockade (Antonaccio and Gomoll, 1993) is unclear, but it is considered that the QT-prolonging effect of dl-sotalol might be caused, at least partially, through a mechanism other than direct hERG inhibition.…”

Stereochemical facets of clinical β‐blockers: An overview

“…As the proteins are chiral in nature, the binding of β‐blockers may be stereoselective. In case some β ‐ blockers like acebutolol, pindolol, and sotalol have their higher free fraction in plasma; the binding of β ‐ blockers to the plasma protein appears to be nonstereoselective.…”