Pang Laboratory Wins Best Article Award From Drug Metabolism and Disposition

A paper written by Postdoctoral Fellow Dr. Edwin Chow of Professor K. Sandy Pang’s laboratory at the Leslie Dan Faculty of Pharmacy was recently recognized as the best pharmacokinetics and drug transporter articles published in Drug Metabolism and Disposition for 2016.

“Functional integrity of the chimeric (humanized) mouse liver: enzyme zonation, physiological spaces, and hepatic enzymes and transporters” was selected from all of the peer-reviewed articles published in the journal last year, and is the product of a collaboration between the Pang laboratory, the Pharmacokinetics, Dynamics & Metabolism group, Johnson and Johnson of Janssen Pharmaceuticals Inc., and In Vitro ADMET Laboratories.

The work investigated the complexity of the chimeric (humanized) liver mouse models to determine whether they are useful in vivo tools for the study of human drug metabolism. The triple knockout FRGN [Fah(-/-), Rag2(-/-), and Il2rg(-/-), NOD strain] mouse that is immune-compromised for the inoculation of human hepatocytes, has been developed for human drug metabolism and toxicity studies, especially for the characterization of new drug entities in drug development. Liver perfusion studies were conducted with FRGN (control) livers and chimeric livers that were repopulated with mouse (mFRGN) or human (hFRGN) hepatocytes to examine liver integrity and the microcirculation. The results showed that the zonal distribution of sulfation and glucuronidation enzymes in the liver (divided into zones 1, 2, and 3) was lost.  With prograde and retrograde perfusion, it was revealed that the harmol conjugation enzymes lacked zonal demarcation for the mFRGN and hFRGN livers, although a higher distribution of sulfation enzymes that preceded the glucuronidation enzymes was found in the control FRGN livers.  Moreover, mouse enzymes and transporters persisted in hFRGN livers.  The study on the microcirculation of the liver with non-eliminated reference indicators (51Cr-RBC, 125I-albumin, 14C-sucrose and 3H-water) revealed the preservation of flow-limited distribution but reduced water and albumin spaces in hFRGN when compared to FRGN livers, a view supported by tightly packed sinusoids microscopically. The lack of checked hepatocyte growth and instability and other disrupted signaling in the hFRGN preparation was explained in a subsequent paper, “Disrupted murine gut-to-human liver signaling alters bile acid homeostasis in humanized mouse liver models,” in the Journal of Pharmacology and Experimental Therapeutics. 

This is the third time that the Pang laboratory was recognized with the best paper award from Drug Metabolism and Disposition. The lab previous received best paper awards for “Localization of glutathione conjugation activities towards bromosulfophthalein in perfused rat liver: Studies with the multiple indicator dilution technique” in 1993 and “A new physiologically-based segregated flow model to explain route-intestinal metabolism” in 2000.