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Hematologic disposition of hydroxychloroquine enantiomers
D R Brocks1, K J Skeith, C Johnston
1Faculty of Pharmacy, University of Alberta, Edmonton, Canada.
Journal of Clinical Pharmacology
|November 1, 1994
Summary
Therapeutic drug monitoring of hydroxychloroquine (HCQ) is best achieved using serum concentrations, as HCQ enantiomers distribute stereoselectively in vivo, unlike in vitro findings. Serum levels correlate best with mononuclear cells, the proposed site of action.
Area of Science:
- Pharmacology
- Drug Metabolism and Distribution
- Analytical Chemistry
Background:
- Hydroxychloroquine (HCQ) is a racemic antiarthritic drug with a long half-life.
- Understanding HCQ distribution in blood fractions is crucial for effective therapeutic drug monitoring (TDM).
- Previous studies have not fully elucidated the stereoselective distribution of HCQ enantiomers in human blood components.
Purpose of the Study:
- To investigate the relationships between hydroxychloroquine (HCQ) concentrations in plasma, serum, and whole blood.
- To determine the optimal blood fraction for therapeutic drug monitoring of HCQ.
- To analyze the stereoselective distribution of HCQ enantiomers in various human blood fractions under in vivo and in vitro conditions.
Main Methods:
- Comparative analysis of HCQ enantiomer concentrations in plasma, serum, whole blood, leukocytes, erythrocytes, and platelets.
- In vitro incubation of separated blood cells with HCQ.
- In vivo studies of HCQ enantiomer distribution and stereoselectivity.
- Analysis of plasma-protein binding and correlation with urinary excretion.
Main Results:
- Serum exhibited substantially higher HCQ enantiomer concentrations than plasma due to platelet activation.
- In vitro, leukocytes showed high HCQ uptake, while erythrocytes and platelets showed low uptake, with R:S ratios near unity.
- In vivo, HCQ concentrations were lower and stereoselective (R:S ratio = 2), with minimal drug in polymorphonuclear cells (PMNs).
- Plasma-protein binding was stereoselective, dependent on alpha 1-acid glycoprotein.
- Serum concentrations correlated best with mononuclear cells (lymphocytes and monocytes).
Conclusions:
- Serum is the preferred blood fraction for therapeutic drug monitoring of hydroxychloroquine (HCQ).
- In vivo HCQ distribution is stereoselective and differs significantly from in vitro findings.
- Serum HCQ concentrations provide a more reliable indicator of drug levels at the proposed site of action (mononuclear cells).