TY  - JOUR
A1  - Rau, Monika
A1  - Schmitt, Johannes
A1  - Berg, Thomas
A1  - Kremer, Andreas E.
A1  - Stieger, Bruno
A1  - Spanaus, Katharina
A1  - Bengsch, Bertram
A1  - Romero, Marta R.
A1  - Marin, Jose J.
A1  - Keitel, Verena
A1  - Klinker, Hartwig
A1  - Tony, Hans-Peter
A1  - Müllhaupt, Beat
A1  - Geier, Andreas
T1  - Serum IP-10 levels and increased DPPIV activity are linked to circulating CXCR3+ T cells in cholestatic HCV patients
JF  - PLoS ONE
N2  - Background & aims
Serum interferon-gamma-inducible protein-10 (IP-10) is elevated in cholestatic liver diseases and predicts response to antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. Dipeptidylpeptidase 4 (DPPIV) cleaves active IP-10 into an inactive form, which inhibits recruitment of CXCR3+ T cells to the liver. In this study the link between IP-10 levels, DPPIV activity in serum and CXCR3+ T cells is analysed in cholestatic and non-cholestatic liver patients.

Methods
In serum DPPIV activity (by enzymatic assay), IP-10 (by ELISA) and bile acids (BA) (by enzymatic assay) were analysed in 229 naive HCV genotype (GT) 1 patients and in 16 patients with cholestatic liver disease. In a prospective follow-up (FU) cohort of 27 HCV GT 1 patients peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ cells were measured by FACS.

Results
In 229 HCV patients serum IP-10 levels correlated positively to DPPIV serum activity. Higher IP-10 levels and DPPIV activity were detected in cholestatic and in cirrhotic HCV patients. Increased IP-10 serum levels were associated with therapeutic non-response to antiviral treatment with pegylated-interferon and ribavirin. In the HCV FU cohort elevated IP-10 serum levels and increased BA were associated with higher frequencies of peripheral CD3+CXCR3+, CD4+CXCR3+ and CD8+CXCR3+ T cells. Positive correlation between serum IP-10 levels and DPPIV activity was likewise validated in patients with cholestatic liver diseases.

Conclusions
A strong correlation between elevated serum levels of IP-10 and DPPIV activity was seen in different cholestatic patient groups. Furthermore, in cholestatic HCV patients a functional link to increased numbers of peripheral CXCR3+ immune cells could be observed. The source of DPPIV release in cholestatic patients remains open.
KW  - hepatitis C virus
KW  - T cells
KW  - liver diseases
KW  - chemokines
KW  - cytotoxic T cells
KW  - immune cells
KW  - cirrhosis
KW  - bile
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177674
VL  - 13
IS  - 12
ER  - 
TY  - JOUR
A1  - Schlauersbach, Jonas
A1  - Hanio, Simon
A1  - Raschig, Martina
A1  - Lenz, Bettina
A1  - Scherf-Cavel, Oliver
A1  - Meinel, Lorenz
T1  - Bile and excipient interactions directing drug pharmacokinetics in rats
JF  - European Journal of Pharmaceutics and Biopharmaceutics
N2  - Bile solubilization plays a major role in the absorption of poorly water-soluble drugs. Excipients used in oral drug formulations impact bile-colloidal properties and their molecular interactions. Polymer-induced changes of bile colloids, e.g., by Eudragit E, reduced the flux of the bile interacting drug Perphenazine whereas bile non-interacting Metoprolol was not impacted. This study corroborates these in vitro findings in rats. Eudragit E significantly reduced systemic availability of Perphenazine but not Metoprolol compared to the oral administrations without polymer. This study confirms the necessity to carefully select polymers for bile interacting drugs whereas non-bile interacting drugs are more robust in terms of excipient choice for formulation. The perspective of bile interaction may introduce interesting biopharmaceutical leverage for better performing oral formulations of tomorrow.
KW  - in vitro-in vivo correlation
KW  - pharmacokinetics
KW  - bile
KW  - excipient
KW  - rat study
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-296969
VL  - 178
ET  - accepted version
ER  -