Importance of Drug Pharmacokinetics at the Site of Action

• Published in: Clinical and translational science Vol. 10; no. 3; pp. 133 - 142
• Main Authors: Rizk, ML, Zou, L, Savic, RM, Dooley, KE
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-05-2017; John Wiley and Sons Inc
• Subjects: Animals; Brain; Cerebrospinal fluid; Disease; Dose-Response Relationship, Drug; Drugs; Genital tract; HIV; Human immunodeficiency virus; Humans; Lungs; Medical research; Membrane Transport Proteins - metabolism; Models, Biological; Pharmaceutical industry; Pharmaceutical Preparations - administration & dosage; Pharmaceutical Preparations - metabolism; Pharmacokinetics; Pharmacology; Physicochemical properties; Physiology; Plasma; Proteins; Review; Serotonin; Tissue Distribution; Urine
• ISSN: 1752-8054; 1752-8062
• DOI: 10.1111/cts.12448

CSF as well as variability in penetration of drugs to the brain and CSF related to inflammation and breakdown of vascular integrity, the dynamics of drug concentrations in CSF cannot generally be extrapolated from plasma concentration data or accurately estimated from a single CSF‐to‐plasma paired‐sample ratio. [...]CSF collected via lumbar puncture is often not a good proxy for drug concentrations in brain extracellular fluid (ECF) (drugs are pumped out of the brain into CSF, and CSF is produced cranially and then flows caudally). [...]in order to understand the potential for a regimen to be effective for PrEP, and, at the same time, to indirectly gain information on regimen adherence, PK measurement at the sites of potential exposure to HIV, namely, the colorectum and female genital tract (FGT), is highly informative. The relative ratio of ELF to plasma concentration can be influenced by many drug properties, including plasma protein binding, the role of transporters in drug uptake and efflux, and the physicochemical properties of the molecule. [...]it is important to compare drug levels in the ELF to free drug levels in the plasma to gain a more robust understanding of lung penetration and translation. Conversely, drugs may be more concentrated in certain cell types through transporter‐mediated penetration. [...]to achieve better therapeutic outcome, it is important to understand the role of transporters as determinants of drug concentrations at the site of action.