Semi-Mechanistic Population Pharmacokinetic Modeling of L-Histidine Disposition and Brain Uptake in Wildtype and Pht1 Null Mice

• Published in: Pharmaceutical research Vol. 35; no. 1; pp. 19 - 9
• Main Authors: Wang, Xiao-Xing, Li, Yang-Bing, Feng, Meihua R., Smith, David E.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.01.2018; Springer; Springer Nature B.V
• Subjects: Animals; Biochemistry; Biological Transport; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Blood-Brain Barrier; Body Fluids - drug effects; Brain; Brain - drug effects; Cerebrospinal fluid; Drug delivery; Drug delivery systems; Drugs; Histidine; Histidine - administration & dosage; Histidine - chemistry; Histidine - pharmacokinetics; Humans; Kinetics; Medical Law; Membrane Transport Proteins - genetics; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; Parenchyma; Parenchymal Tissue - drug effects; Pharmacokinetics; Pharmacology/Toxicology; Pharmacy; Research Paper; Rodents; Substrates; Tissue Distribution; Vehicles; PHT1; L-histidine; brain parenchyma; mice; population pharmacokinetics
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-017-2322-0

Purpose To develop a semi-mechanistic population pharmacokinetic (PK) model to quantitate the disposition kinetics of L-histidine, a peptide-histidine transporter 1 (PHT1) substrate, in the plasma, cerebrospinal fluid and brain parenchyma of wildtype (WT) and Pht1 knockout (KO) mice. Methods L-[ 14 C]Hisidine (L-His) was administrated to WT and KO mice via tail vein injection, after which plasma, cerebrospinal fluid (CSF) and brain parenchyma samples were collected. A PK model was developed using non-linear mixed effects modeling (NONMEM). The disposition of L-His between the plasma, brain, and CSF was described by a combination of PHT1-mediated uptake, CSF bulk flow and first-order micro-rate constants. Results The PK profile of L-His was best described by a four-compartment model. A more rapid uptake of L-His in brain parenchyma was observed in WT mice due to PHT1-mediated uptake, a process characterized by a Michaelis-Menten component (V max  = 0.051 nmoL/min and K m  = 34.94 μM). Conclusions A semi-mechanistic population PK model was successfully developed, for the first time, to quantitatively characterize the disposition kinetics of L-His in brain under in vivo conditions. This model may prove a useful tool in predicting the uptake of L-His, and possibly other PHT1 peptide/mimetic substrates, for drug delivery to the brain.