Effect of peginterferon alfa-2a (40KD) on cytochrome P450 isoenzyme activity.
ABSTRACT AIM: Pegylated interferon-based therapy is recommended for treatment of hepatitis C virus (HCV) infection. Because interferons are known to downregulate hepatic cytochrome P450 (CYP) enzymes, which are involved in drug metabolism and clearance, there is a need to investigate the effect of peginterferon (PEG-IFN) alfa-2a (40KD) on the activity of these enzymes in the CYP system. METHODS: Fourteen healthy, male volunteers aged 18 to 45 years were recruited into an open-label, two-period, single-centre study in which CYP enzyme activity was measured by administration of the selectively metabolised probe drugs theophylline (CYP1A2), tolbutamide (CYP2C9), mephenytoin (CYP2C19), debrisoquine (CYP2D6) and dapsone (CYP3A4) on day 1 of the study. Peginterferon alfa-2a (40KD) 180 μg was given subcutaneously each week from day 15 to 36, and probe drugs were re-administered on day 37. Probe drugs and metabolites were quantified in plasma or urine samples and used to derive enzyme activity and pharmacokinetic parameters. RESULTS: Peginterferon alfa-2a (40KD) significantly increased the area under the serum drug concentration versus time curve (AUC(0-∞) ) for theophylline by 24%, with a reduction in the mean oral clearance of theophylline of 20%. There were no effects on the pharmacokinetics of any of the other probe drugs. The incidence of adverse events was as expected in subjects receiving pegylated interferons. CONCLUSION: These results suggest there may be an inhibitory effect of PEG-IFN alfa-2a (40KD) on CYP1A2. Peginterferon alfa-2a (40KD) had no effect on CYP2C9, CYP2C19, CYP2D6 or CYP3A4 in healthy patients.
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ABSTRACT: Mathematical models of hepatitis C virus (HCV) during therapy may elucidate mechanisms of action for antiviral therapy. In genome-wide association studies, IL28B gene polymorphisms are highly predictive of therapeutic clearance of HCV. We collected sera from 20 chronically infected HCV participants at 13 points during the first 28 days of therapy. We assessed the presence of the C allele at single-nucleotide polymorphism rs12979860 using the ABI TaqMan allelic discrimination kit. We estimated dynamic parameters from the entire population using the Neumann model for HCV infection. Statistical methods for repeated nonlinear measures compared model parameters by established predictors of response. The frequencies of IL28B genotypes were 6 (C/C), 11 (C/T), and 3 (T/T). The mean log decline in HCV RNA from 0 to 48 hours was more rapid among C/C genotype participants compared with C/T or T/T genotype participants (1.4 vs 0.7; P = .07), and from 2 days to 14 days (1.6 vs 0.7; P = .04). In the multivariate model, the C/C genotype predicted a steeper second-phase decline when adjusted for race (P = .01). The presence of the C/C genotype at IL28B rs12979860 exerts its antiviral effect by increasing the infected hepatocyte death rate. This suggests that an immune-mediated mechanism is responsible.The Journal of Infectious Diseases 08/2011; 204(3):419-25. · 5.85 Impact Factor
- Hepatology 05/2004; 39(4):1147-71. · 11.19 Impact Factor
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ABSTRACT: Variability of drug metabolism, especially that of the most important phase I enzymes or cytochrome P450 (CYP) enzymes, is an important complicating factor in many areas of pharmacology and toxicology, in drug development, preclinical toxicity studies, clinical trials, drug therapy, environmental exposures and risk assessment. These frequently enormous consequences in mind, predictive and pre-emptying measures have been a top priority in both pharmacology and toxicology. This means the development of predictive in vitro approaches. The sound prediction is always based on the firm background of basic research on the phenomena of inhibition and induction and their underlying mechanisms; consequently the description of these aspects is the purpose of this review. We cover both inhibition and induction of CYP enzymes, always keeping in mind the basic mechanisms on which to build predictive and preventive in vitro approaches. Just because validation is an essential part of any in vitro-in vivo extrapolation scenario, we cover also necessary in vivo research and findings in order to provide a proper view to justify in vitro approaches and observations.Archives of Toxicology 08/2008; 82(10):667-715. · 5.08 Impact Factor