Enantioselective gallopamil protein binding

Abstract

The protein binding of the enantiomers of gallopamil has been investigated in solutions of human serum albumin, alpha 1-acid glycoprotein and serum. Over the range of concentrations attained after oral gallopamil administration, the binding of both enantiomers to albumin, alpha 1-acid glycoprotein, and serum proteins was independent of gallopamil concentration. The binding to both human serum albumin (40 g/liter) [range of fraction bound (fb) R: 0.624 to 0.699; S: 0.502 to 0.605] and alpha 1-acid glycoprotein (0.5 g/liter) (range of fb R: 0.530 to 0.718; S: 0.502 to 0.620) was stereoselective, favoring the (R)-enantiomer (predialysis gallopamil concentrations 2.5 to 10,000 ng/ml). When the enantiomers (predialysis gallopamil concentration 10 ng/ml) were studied separately in drug-free serum samples from six healthy volunteers the fraction of (S)-gallopamil bound (fb: 0.943 +/- 0.016) was lower (P < 0.05) than that of (R)-gallopamil (fb: 0.960 +/- 0.010). The serum protein binding of both (R)- and (S)-gallopamil was unaffected by their optical antipodes (fb R: 0.963 +/- 0.011; S: 0.948 +/- 0.015) indicating that at therapeutic concentrations a protein binding enantiomer-enantiomer interaction does not occur. The protein binding of (R)- and (S)-gallopamil ex vivo 2 h after single dose oral administration of 50 mg pseudoracemic gallopamil (fb R: 0.960 +/- 0.010: predialysis [R] 6.9 to 35.3 ng/ml; S: 0.943 +/- 0.016: predialysis [S] 9.5 to 30.7 ng/ml) was comparable to that observed in vitro in drug-free serum. Gallopamil metabolites formed during first-pass following oral administration, therefore, do not influence the protein binding of (R)- or (S)-gallopamil.

Pharmacokinetics and pharmacodynamics of R‐ and S‐gallopamil during multiple dosing

“…These differences at steady‐state confirm the stereoselectivity previously observed after administration of a single dose of pseudoracemic gallopamil [3]. The higher free fraction of S‐gallopamil is a consequence of interactions with both albumin and α 1 ‐acid glycoprotein [11], and contributes to the higher renal excretion of S‐than R‐gallopamil observed.…”

“…After dose 7 the heart rate, blood pressure, electrocardiogram and peripheral blood flow in both legs (Infraton Vasoskript, Boucke, Germany) were monitored at 15 min intervals for 5 h postdose. R‐ and S‐gallopamil protein binding in serum samples collected 2 h after the final dose of gallopmil was determined by equilibrium dialysis [11].…”