Featured research (5)

Calcitriol, a vitamin D3 metabolite, is approved for various indications because it is the bioactive form of vitamin D in the body. The purpose of this study was to predict the clinical significance of cytochrome P450 (CYP) induction by calcitriol using in vitro human cryopreserved hepatocytes, HepaRG experimental systems, and various pharmacokinetic estimation models. CYP2B6, 3A4, 2C8, and 2C9 mRNA levels increased in a concentration-dependent manner in the presence of calcitriol in human cryopreserved hepatocytes and HepaRG cells. Using the half maximal effective concentration (EC50) and maximum induction effect (Emax) obtained from the in vitro study, a basic kinetic model was applied, suggesting clinical relevance. In addition, a static mechanistic model showed the improbability of a clinically significant effect; however, the calculated area under the plasma concentration–time curve ratio (AUCR) was marginal for CYP3A4 in HepaRG cells. To clarify the effect of CYP3A4 in vivo, physiologically based pharmacokinetic (PBPK) modeling was applied as a dynamic mechanistic model, revealing a low clinically significant effect of CYP3A4 induction by calcitriol. Therefore, we conclude that CYP induction by calcitriol treatment would not be clinically significant under typical clinical conditions.
We investigated whether human serum albumin (HSA) in suspended human hepatocytes would affect the uptake clearance of anionic drugs with high binding to HSA and improve the extrapolation of in vivo hepatic clearance from in vitro uptake clearance by the hepatocytes via the "albumin-mediated" hepatic uptake mechanism. The uptake clearances for total forms (PSinf) and for unbound forms (PSu,inf) of 11 anionic drugs [all of which were organic anion-transporting polypeptide (OATP) substrates] were determined with suspended human hepatocytes in varying concentrations of HSA. The fraction of unbound drugs (fu) was determined using an equilibrium dialysis at the various HSA concentrations. The PSinf values decreased with increasing concentrations of HSA, whereas the unbound uptake clearances (PSu,inf(+) = PSinf/ fu) in the presence of HSA increased substantially, thus demonstrating the "albumin-mediated" hepatic uptake mechanism. The relationships between PSinf and HSA concentration were well described by the previously proposed facilitated-dissociation model, in which the drug-albumin complex interacts with the cell surface, enhancing the dissociation of the complex and providing unbound drug for hepatic uptake. Furthermore, the PSu,inf (+) values in in vivo conditions (at 5% HSA) were predicted from those obtained in isolated hepatocytes on the basis of the facilitated-dissociation model, revealing compatibility with the overall hepatic intrinsic clearance in vivo. We conclude that the "facilitated-dissociation" model is useful for describing the "albumin-mediated" hepatic uptake phenomenon of OATP drugs and to predict hepatic uptake clearance in vivo. Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.
• The purpose of this study was to evaluate the acute effect of a small molecule inhibitor of DGAT-1 on triglycerides and cholesterol in polygenic type 2 diabetic TallyHo/JngJ (TH) mice. PF-04620110, a potent and selective DGAT-1 inhibitor, was used as a model compound in this study and which was administered to TH and ICR mice. • The concentration of the model compound that produced 50% of maximum lowering of triglyceride level (IC50) in TH mice was not significantly different from that in ICR mice, when estimated using the model-based pharmacokinetic and pharmacodynamic assay, a 2-compartmental model and an indirect response model. • The clearance of the inhibitor in TH mice was 5-fold higher than that in ICR mice, suggesting significantly altered pharmacokinetics. Moreover, the in vitro metabolic elimination kinetic parameters (ke,met), determined using liver microsomes from TH and ICR mice were 1.24 ± 0.14 and 0.174 ± 0.116 min⁻¹, respectively. • Thus, we report that the differences in the acute effects of the small molecule DAGT-1 inhibitor between TH mice and ICR mice can be attributed to altered pharmacokinetics caused by an altered metabolic rate for the compound in TH mice.
The objective of this study was to evaluate the permeability of small molecules into the brain via the blood-brain barrier in zebrafish and to investigate the possibility of using this animal model as a screening tool during the early stages of drug discovery. Fifteen compounds were used to understand the permeation into the brain in zebrafish and mice. The ratio of brain-to-plasma concentration was compared between the two animal models. The partition coefficient (Kp,brain), estimated using the concentration ratio at designated times (0.167, 0.25, 0.5, or 2 h) after oral administrations (per os, p.o), ranged from 0.099 to 5.68 in zebrafish and from 0.080 to 11.8 in mice. A correlation was observed between the Kp,brain values obtained from the zebrafish and mice, suggesting that zebrafish can be used to estimate Kp,brain to predict drug penetration in humans. Furthermore, in vivo transport experiments to understand the permeability glycoprotein (P-gp) transporter-mediated behavior of loperamide (LPM) in zebrafish were performed. The zebrafish, Kp,brain,30min of LPM was determined to be 0.099 ± 0.069 after dosing with LPM alone, which increased to 0.180 ± 0.115 after dosing with LPM and tariquidar (TRQ, an inhibitor of P-gp). In mouse, the Kp,brain,30min of LPM was determined to be 0.080 ± 0.004 after dosing with LPM alone and 0.237 ± 0.013 after dosing with LPM and TRQ. These findings indicate that the zebrafish could be used as an effective screening tool during the discovery stages of new drugs to estimate their distribution in the brain.
The objective of this study was to characterize the systemic and tissue kinetics of 2-(3,4-dimethoxyphenyl)-5-(3-methoxypropyl) benzofuran (SNU-0039), an inhibitor of β-amyloid protein aggregation, in rats. Simultaneous fitting of the data to polyexponential equations indicated that the systemic clearance and steady state volume of distribution were estimated to be 0.0220 l/min/kg and 2.33 l/kg. The clearance and volume of distribution were not dependent on the intravenous dose, in the range from 5 to 20 mg/kg. The tissue (i.e., the brain, liver, kidneys, heart, spleen, lungs, gut, muscle and adipose tissue) to plasma partition coefficients (K p ) for SNU-0039 in rats ranged from a low of 0.779 ± 0.314 (muscle) to a high of 5.71 ± 1.66 (liver). The recoveries of DMB were less than 1% of the dose for the renal and biliary excretion, indicative of minor involvements of these pathways in overall elimination. The fraction of bound SNU-0039 to plasma protein was approximately 95.9% and the fraction of SNU-0039 distributed to blood cells was approximately 45.3%. Assuming a flow-limited distribution, the simulated concentration profiles for SNU-0039 in the physiologically based pharmacokinetic model were in reasonable agreement with the observed concentrations in plasma and nine tissues in rats.

Lab head

Kyeong-Ryoon Lee
Department
  • Laboratory of Pharmacokinetics

Members (1)

Jong-Woo Jeong
  • Korea Institute of Toxicology
Min Ju Kim
Min Ju Kim
  • Not confirmed yet
Yoo-Kyung Song
Yoo-Kyung Song
  • Not confirmed yet
Seop Lee
Seop Lee
  • Not confirmed yet

Alumni (1)

Song-Hee Chae
Song-Hee Chae