Physiologically Based Pharmacokinetics of Lysosomotropic Chloroquine in Rat and Human.

A semimechanistic physiologically based pharmacokinetic (PBPK) model for chloroquine (CQ), a highly lysosomotropic weak base, was applied to digitized rat and human concentration versus time data. The PBPK model in rat featured plasma and red blood cell (RBC) concentrations, extensive and apparent nonlinear tissue distribution, fitted hepatic and renal intrinsic clearances, and a plasma half-life of about 1 day. Tissue-to-plasma CQ ratios at 50 hours after dosing were highest in lung, kidney, liver, and spleen (182-318) and lower in heart, muscle, brain, eye, and skin (11-66). The RBC-to-plasma ratio of 11.6 was assumed to reflect cell lipid partitioning. A lysosome-based extended model was used to calculate subcellular CQ concentrations based on tissue mass balances, fitted plasma, interstitial and free cytosol concentrations, and literature-based pH and pKa values. The CQ tissue component concentrations ranked as follows: lysosome > > acidic phospholipid > plasma = interstitial = cytosol ≥ neutral lipids. The extensive lysosome sequestration appeared to change over time and was attributed to lowering pH values caused by proton pump influx of hydrogen ions. The human-to-rat volume of distribution () ratio of 7 used to scale rat tissue partitioning to human along with estimation of hepatic clearance allowed excellent fitting of oral-dose PK (150-600 mg) of CQ with a 50-day half-life in humans. The prolonged PK of chloroquine was well characterized for rat and human with this PBPK model. The calculated intratissue concentrations and lysosomal effects have therapeutic relevance for CQ and other cationic drugs. SIGNIFICANCE STATEMENT: Sequestration in lysosomes is a major factor controlling the pharmacokinetics and pharmacology of chloroquine and other cationic drugs. This report provides comprehensive physiologic modeling of chloroquine distribution in tissues and overall disposition in rat and human that reveals expected complexities and inferences related to its subcellular association with various tissue components.