Enantioselective plasma protein binding of propafenone: Mechanism, drug interaction, and species difference

Abstract

The interaction of propafenone (PPF) enantiomers with human plasma, human serum albumin (HSA), alpha(1)-acid glycoprotein (AGP), as well as with plasma from rat, rabbit, and cow was investigated using indirect chiral high performance liquid chromatography (HPLC) and ultrafiltration techniques. The stronger binding of the S-PPF found in human plasma was due to AGP. Two classes of binding sites in AGP were identified: one with high-affinity and small binding capacity (K(1(S)) = 7.65 x 10(6) M(-1), n(1(S)) = 0.50; K(1(R)) = 2.81 x 10(6) M(-1), n(1(R)) = 0.46), which revealed stereoselectivity; the other with low-affinity and high-binding capacity (n(2(S)) K(2(S)) = 9.95 x 10(3) M(-1); n(2(R)) K(2(R)) = 9.74 x 10(3) M(-1)). The binding to HSA was found to be weak and not enantioselective (nK(S) = 2.08 x 10(3) M(-1), nK(R) = 2.05 x 10(3) M(-1)). The interaction between enantiomers observed in human plasma was confirmed as a competitive type interacting at the high-affinity site in AGP. The binding mode of both enantiomers with AGP was mainly hydrophobic bond. PPF enantiomers had higher-binding affinity for the F-S variant of human AGP. Drug-drug binding interaction studies showed that verapamil, diazepam, nifedipine, furosemide, nitrendipine, and nimodipine did not affect the binding of PPF enantiomers except quinidine and aprindine at the therapeutic concentration. Comparative studies indicated considerable species-dependent binding stereoselectivity between plasma of the four species investigated.

Stereoselective binding of mexiletine and ketoprofen enantiomers with human serum albumin domains

“…Over 50% of the drugs in current clinical use are chiral, and the majority of synthetically derived chiral drugs are administered as mixtures of the constituent stereoisomers (most commonly the racemate) [2] . In addition to stereoselective metabolism, stereoselective protein binding might also be responsible for the differences in pharmacokinetics between enantiomers [3][4][5] . Studies on the mechanism of stereoselective binding to HSA may better explain the different pharmacokinetics between enantiomers.…”

In Vitro–In Vivo Extrapolation of Clearance: Modeling Hepatic Metabolic Clearance of Highly Bound Drugs and Comparative Assessment with Existing Calculation Methods

“…For the current drugs, the observed value of fu p ranged from 0.0007 to 0.15, whereas human CL ranged from 0.04 to 15 mL/(min kg), covering a large range of properties for highly bound compounds. 2,10,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] The dataset is compiled in Table 1. Clearance refers to plasma kinetics, and it was assumed that this is mainly due to hepatic metabolic CL.…”

“…For each drug studied, the main extracellular binding protein considered in this study is AL or AAG [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] (Table 1). However, the works of Burczynski et al, 13 Qin et al, 38 and Bilello et al 39 suggest that proteinfacilitated metabolism, and hence hepatocyte uptake of drugs, is significantly greater with AL as compared with that of AAG at physiologically relevant concentrations (more explanations are provided in the Discussion section for differences between AL and AAG).…”

Enantioselective analysis of unbound tramadol, O-desmethyltramadol and N-desmethyltramadol in plasma by ultrafiltration and LC–MS/MS: Application to clinical pharmacokinetics

“…Since the binding of drugs to plasma proteins can be stereoselective [11,12], the present study describes, for the first time, the analysis of unbound concentrations of the tramadol, M1 and M2 enantiomers in human plasma and the application of this method to pharmacokinetic studies on patients with neuropathic pain treated with a single dose of racemic tramadol. The method described is derived from a study recently published by our group in which total concentrations of the tramadol, M1 and M2 enantiomers were analyzed in rat plasma [13].…”