Direct and cytokine‐mediated effects of albumin‐fused growth hormone, TV‐1106, on CYP enzyme expression in human hepatocytes in vitro

Abstract

Some biologics can modulate cytokines that may lead to changes in expression of drug‐metabolizing enzymes and cause drug‐drug interactions (DDI). DDI potential of TV‐1106—an albumin‐fused growth hormone (GH)—was investigated. In this study, human blood was exposed to recombinant human growth hormone (rhGH) or TV‐1106, followed by isolation of the plasma and its application to human hepatocytes. While the treatment of blood with rhGH increased multiple cytokines, treatment of blood with TV‐1106 had no effect on any of the nine cytokines tested. The interleukin (IL)‐6 concentration was higher in the rhGH then in the TV‐1106‐treated plasma (P < .05). While rhGH had little or no effect on CYP1A2 or CYP2C19 mRNA but increased CYP3A4 mRNA twofold, TV‐1106 had little or no effect on cytochrome P450 (CYP) mRNAs in hepatocytes. Although the plasma from rhGH‐treated blood lowered CYP1A2 activity, the TV‐1106 plasma had no effect on CYP activities. The CYP1A2 activity was lower in the rhGH‐ then in the TV‐1106‐plasma treated hepatocytes (P < .05). The results indicated that fusing GH with albumin made TV‐1106 an unlikely participant of CYP1A2, CYP2C19 or CYP3A4‐facilitated, direct or cytokine‐driven DDI.

Clinical and Molecular Perspectives on Inflammation‐Mediated Regulation of Drug Metabolism and Transport

“…The in vitro effect of IL‐6 on the mRNA expression of CYP enzymes in primary human hepatocytes have been reported in multiple studies 25‐43 . IL‐6 substantially downregulates the mRNA expression of CYP3A4 up to 100‐fold at 10 ng/mL, 26–28,30–32,34–43 whereas other CYP enzymes are downregulated 1.5‐ to 8‐fold by 10 ng/mL IL‐6 26–28,31,34,35,37–43 .…”

“…[25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] IL-6 substantially downregulates the mRNA expression of CYP3A4 up to 100-fold at 10 ng/mL, [26][27][28][30][31][32][34][35][36][37][38][39][40][41][42][43] whereas other CYP enzymes are downregulated 1.5-to 8-fold by 10 ng/mL IL-6. [26][27][28]31,34,35,[37][38][39][40][41][42][43] A study reported a 2-fold upregulation of CYP2D6 mRNA by IL-6, 34 however, two other studies reported a maximum of 2to 3-fold downregulation of CYP2D6 mRNA at the same IL-6 concentration.…”

“…The in vitro effect of IL-6 on the mRNA expression of CYP enzymes in primary human hepatocytes have been reported in multiple studies. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] IL-6 substantially downregulates the mRNA expression of CYP3A4 up to 100-fold at 10 ng/mL, [26][27][28][30][31][32][34][35][36][37][38][39][40][41][42][43] whereas other CYP enzymes are downregulated 1.5-to 8-fold by 10 ng/mL IL-6. [26][27][28]31,34,35,[37][38][39][40][41][42][43] A study reported a 2-fold upregulation of CYP2D6 mRNA by IL-6, 34 howe...…”

“…33,37 In line with the reduced expression of CYP enzymes, IL-6 leads to downregulation of CYP enzyme activity in primary human hepatocytes. 25,27,29,[32][33][34][35][36][37][38]40,41 CYP3A4 activity is markedly downregulated up to 50-fold by 10 ng/mL IL-6, whereas the enzyme activity of other CYP enzymes is downregulated 1.5-to 7-fold.…”

“…The in vitro effect of IL‐6 on the mRNA expression of CYP enzymes in primary human hepatocytes have been reported in multiple studies 25‐43 . IL‐6 substantially downregulates the mRNA expression of CYP3A4 up to 100‐fold at 10 ng/mL, 26–28,30–32,34–43 whereas other CYP enzymes are downregulated 1.5‐ to 8‐fold by 10 ng/mL IL‐6 26–28,31,34,35,37–43 . A study reported a 2‐fold upregulation of CYP2D6 mRNA by IL‐6, 34 however, two other studies reported a maximum of 2‐ to 3‐fold downregulation of CYP2D6 mRNA at the same IL‐6 concentration 33,37 .…”