Factors affecting quinidine protein binding in humans.

Area of Science:

• Pharmacology
• Clinical Chemistry
• Drug Metabolism

Background:

• The unbound drug concentration in plasma is a key determinant of pharmacological and toxicological outcomes.
• Previous studies on factors influencing quinidine's free fraction have produced conflicting results, potentially due to methodological biases.
• This research aimed to accurately estimate quinidine binding by minimizing known artifact-inducing factors.

Purpose of the Study:

• To accurately determine the free fraction of quinidine in healthy volunteers and identify its plasma binding characteristics.
• To investigate the influence of human serum albumin and alpha 1-acid glycoprotein on quinidine binding.
• To assess how conditions like traumatic injury and hyperlipidemia affect the free fraction of quinidine.

Main Methods:

• Utilized a study design free from known artifact-introducing factors in blood collection and analysis.
• Quantified quinidine binding by identifying high-affinity, low-capacity, and low-affinity, high-capacity binding sites.
• Measured quinidine free fraction in healthy volunteers and patients with traumatic injury or hyperlipidemia.

Main Results:

• In healthy volunteers, the mean quinidine free fraction was 0.129 ± 0.019, remaining constant within the therapeutic range.
• Two binding sites were identified: a high-affinity site (K = 1.17 X 10(5) M-1) and a low-affinity site (K = 1.33 X 10(3) M-1), with the latter likely associated with human serum albumin.
• Patients with traumatic injury showed a significantly decreased quinidine free fraction (0.075 ± 0.019) correlating with increased alpha 1-acid glycoprotein levels.

Conclusions:

• The study established reliable baseline values for quinidine free fraction in healthy individuals.
• Alpha 1-acid glycoprotein significantly influences quinidine binding, leading to reduced free fractions in conditions like traumatic injury.
• Understanding these binding dynamics is crucial for optimizing quinidine therapy and predicting its efficacy and toxicity.