Influence of the ORM1 phenotypes on serum unbound concentration and protein binding of quinidine
Introduction
Quinidine remains a frequently used drug for treatment of supraventricular and ventricular arrhythmias. With a narrow therapeutic index, monitoring of serum quinidine concentrations is potentially useful to facilitate optimum dosage adjustment, because the pharmacokinetic characteristics vary considerably from one individual to another [1], [2]. However, serum concentrations and clinical effects are not well correlated for some drugs. A major factor may be variability in protein binding of drugs in serum [3]. The degree of protein binding of extensively bound drugs is a major determinant of the intensity and duration of pharmacological action. Only unbound or free drug in plasma can be transported to its site of action or of metabolic alteration or excretion from the body [3], [4]. The difference in plasma protein binding could modify the dynamic properties of a drug in the body, hereafter influence the effects or produce the adverse reactions of the drugs [5]. The protein binding of quinidine is characterized by a marked interindividual variability [6], [7]. The exact reasons for this variability is unclear.
Human α1-acid glycoprotein (α1-AGP), also known as orosomucoid (ORM), is a major binding protein for various basic drugs such as disopyramide, quinidine and amitriptyline in plasma [8]. It has been shown that ORM is coded by two loci, ORM1 and ORM2, which are closely linked on chromosome 9q31→34.1. The ORM1 locus is highly polymorphic and the ORM2 locus is monomorphic in most populations [9], [10]. Three codominant alleles (ORM1*F1, ORM1*F2 and ORM1*S) at ORM1 locus present six ORM1 phenotypes. Three common ORM1 phenotypes presented in population are the homozygotes ORM1 F1 and ORM1 S, and the heterozygote ORM1 F1S [9], [10], [11], [12]. The previous study [12] demonstrated that the ORM1 locus is polymorphic and the ORM2 locus is monomorphic in sera from the Han population of Nanjing, China. For ORM1 locus, the allele frequencies were: ORM1*F1=0.7068, ORM1*F2=0.0182 and ORM1*S=0.2750 [12].
The genetics of drug binding to human plasma proteins and more specifically to ORM has received increasing attention because its knowledge could have insight into the individual variability of the pharmacological response [13], [14]. The functional heterogeneity of ORM could be related to the differences in plasma binding of basic drugs considering that ORM is the main transporter for these drugs in plasma [5], [13], [14].
The purpose of this study was to investigate the influence of ORM1 phenotypes on the serum unbound concentration and protein binding of quinidine.
Section snippets
Instruments and reagents
The chromatographic system consisted of an LC-6A pump, an SPD-6AV UV-detector, and a CR3A integrator (Shimadzu, Japan). Quinidine hydrochloride monohydrate was from Sigma (USA) and quinidine sulfate tablets were from Xinyi Pharmaceutical (Shanghai, China).
Subjects
Twenty-eight healthy male volunteers (age 21.3±1.3 years, weight 62.3±7.5 kg, height 171.5±6.7 cm) with three different serum ORM1 phenotypes (homozygotes ORM1 F1 and ORM1 S, and heterozygote ORM1 F1S) participated in the study (Table 1).
ORM concentrations in sera
Serum ORM concentrations in the 28 healthy male subjects are shown in Table 2. In regard to the three groups of different ORM1 phenotypes, ORM concentrations in sera were 573.2±29.3, 553.8±31.2 and 569.8±40.1 mg/l for ORM1 F1, S and F1S phenotypes, respectively. There was no significant difference in serum ORM concentration for the subjects among three ORM1 phenotypes (P>0.05) (Table 2).
Serum concentrations of total and unbound quinidine
The mean serum concentration–time curves of total quinidine during 0–24 h are summarized in Fig. 1. After
Discussion
It is generally accepted that free (unbound) concentrations are therapeutically more relevant. However, total concentrations are more often reported because of analytical considerations [18]. A basic tenet of biochemical pharmacology is that the intensity and duration of drug action is mediated via the time course of unbound drug concentrations at the site of action. Although direct measurement of unbound drug concentrations at the site of action is seldom possible, the unbound drug
Acknowledgements
This project was supported by the National Natural Science Foundation (No. 39670843) and the Scientific Research Foundation of Ministry of Personnel (1997-201) of China.
The authors thank Mrs. Ming-Hong Cai for her assistance in the collection of blood samples.
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