Depression of drug metabolizing activity in the human liver by interferon-?

Okuno, Hiroyasu; Kitao, Yuko; Takasu, Masashi; Kano, Haruhiko; Kunieda, K; Seki, Toshihito; Shiozaki, Yasuko; Sameshima, Yoshiko

doi:10.1007/bf00315411

Cited by 56 publications

(28 citation statements)

References 17 publications

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“…The related interferon-, has also been shown by Okuno et al [23] to decrease TH clearance by 20% after high dose daily injections. Williams & Farrell [12] reported a 16% decrease in AP clearance in 9 patients with chronic active hepatitis after an acute dose of intramuscular IFNct.…”

Section: Discussionmentioning

confidence: 81%

Effects of interferon‐alpha monotherapy on hepatic drug metabolism in cancer patients.

Israel¹,

Blouin²,

McIntyre³

et al. 1993

Brit J Clinical Pharma

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1. The influence of interferon‐alpha (IFN alpha) on the clearances of theophylline (TH), antipyrine (AP) and hexobarbitone (HB) was studied in seven cancer patients given IFN alpha as their only treatment. In addition, IFN alpha effects on drug clearance were correlated with changes in serum inflammatory cytokines and acute phase proteins. 2. A 'baseline' study was performed by administering an oral drug 'cocktail' of TH (150 mg), AP (250 mg) and HB (250 mg) with saline injected simultaneously and again 24 h later. One week later, an 'acute' study was performed at the initiation of IFN alpha therapy, 3 × 10(6) units injected with the drug cocktail and again 24 h later. After 2 weeks of IFN alpha treatment three times per week, a 'chronic' study was performed with IFN alpha injected the day prior to, simultaneously with, as well as 24 h after the drug cocktail. 3. Plasma samples were collected over 48 h and the clearances of TH, AP and HB were estimated. Serum samples were collected at various times for the measurement of tumor necrosis factor (TNF), interleukin‐1 (IL‐1), interleukin‐6 (IL‐ 6), C‐reactive protein (C‐RP) and alpha 1‐acid glycoprotein (AGP). 4. IFN alpha caused a 33% decrease in the oral clearance of TH during the chronic study compared with baseline (P < or = 0.05). Although IFN alpha inhibited TH clearance by 16% during the acute study and AP clearance by 20‐21% during both acute and chronic studies, these changes did not reach statistical significance. IFN alpha caused minimal changes in HB clearance. There were no chronic effects of IFN alpha on serum cytokines or acute phase proteins. 5. The findings confirm that the most commonly used dose of IFN alpha inhibits the hepatic clearance in humans of some but not all drugs and that this inhibition persists during IFN alpha therapy. Because inhibition was not associated with increases in serum cytokines or acute phase proteins, the mechanism by which IFN alpha inhibits cytochrome P450 activities in vivo does not appear to involve inflammatory mediators such as TNF. IL‐1 or IL‐6.

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Section: Discussionmentioning

confidence: 81%

Effects of interferon‐alpha monotherapy on hepatic drug metabolism in cancer patients.

Israel¹,

Blouin²,

McIntyre³

et al. 1993

Brit J Clinical Pharma

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“…A correlation was found between the dose of IFNb and the magnitude of decrease in P450 enzymes; furthermore, the metabolism of other drugs (theophylline) was affected [60]. Buchwalder et al did not find any relevant effects of SC applied IFNb on cytochrome P450 enzymes in healthy subjects; however, in this study, only four doses of IFNb were administered [26].…”

Section: Metabolismmentioning

confidence: 90%

Pharmacokinetic considerations in the treatment of multiple sclerosis with interferon-β

Hegen

Auer

Deisenhammer

2015

Expert Opinion on Drug Metabolism & Toxicology

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IFNβ has a bioavailability of ∼ 30% after subcutaneous or intramuscular administration, shows peak serum concentrations within several hours, has a half-life of < 1 day and is eliminated by a renal and hepatic pathway. PK parameters do not substantially differ between the types of IFNβ and routes of administration; only pegylation of IFNβ results in substantially increased and prolonged PK. Although no clinical dose-effect relationship could be established, there is an association of IFNβ dose with magnetic resonance imaging outcome parameters. Furthermore, there is an association of IFNβ serum levels with the occurrence of adverse events and anti-drug antibodies.

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“…It is possible that the inhibitory effect of delavirdine on ritonavir clearance is more pronounced at the higher ritonavir concentrations, since ritonavir exhibits nonlinear pharmacokinetics (10). Subject differences (healthy volunteers versus HIV-1-infected patients) may also have contributed to the difference between study results regarding the effect of delavirdine on ritonavir clearance; altered patterns of drug metabolism have been observed in HIV-1-infected patients relative to those in normal volunteers (3,4,12,15,16). The concentration-time profiles for delavirdine in the present study generally differed from those in previous steady-state studies with either fasting or fed HIV-1-infected patients, and this difference is consistent with a more delayed and/or prolonged drug absorption (1, 2, 7).…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Ritonavir and Delavirdine in Human Immunodeficiency Virus-Infected Patients

Shelton

Hewitt

Adams

et al. 2003

Antimicrob Agents Chemother

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To evaluate the pharmacokinetic effect of adding delavirdine mesylate to the antiretroviral regimens of human immunodeficiency virus (HIV)-infected patients stabilized on a full dosage of ritonavir (600 mg every 12 h), 12 HIV-1-infected subjects had delavirdine mesylate (400 mg every 8 h) added to their current antiretroviral regimens for 21 days. Ritonavir pharmacokinetics were evaluated before (day 7) and after (day 28) the addition of delavirdine, and delavirdine pharmacokinetics were evaluated on day 28. The mean values (؎ standard deviations) for the maximum concentration in serum (C max ) of ritonavir, the area under the concentration-time curve from 0 to 12 h (AUC 0-12 ), and the minimum concentration in serum (C min ) of ritonavir before the addition of delavirdine were 14.8 ؎ 6.7 M, 94 ؎ 36 M ⅐ h, and 3.6 ؎ 2.1 M, respectively. These same parameters were increased to 24.6 ؎ 13.9 M, 154 ؎ 83 M ⅐ h, and 6.52 ؎ 4.85 M, respectively, after the addition of delavirdine (P is <0.05 for all comparisons). Delavirdine pharmacokinetic parameters in the presence of ritonavir included a C max of 23 ؎ 16 M, an AUC 0-8 of 114 ؎ 75 M ⅐ h, and a C min of 9.1 ؎ 7.5 M. Therefore, delavirdine increases systemic exposure to ritonavir by 50 to 80% when the drugs are coadministered.

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Depression of drug metabolizing activity in the human liver by interferon-?

Cited by 56 publications

References 17 publications

Effects of interferon‐alpha monotherapy on hepatic drug metabolism in cancer patients.

Effects of interferon‐alpha monotherapy on hepatic drug metabolism in cancer patients.

Pharmacokinetic considerations in the treatment of multiple sclerosis with interferon-β

Pharmacokinetics of Ritonavir and Delavirdine in Human Immunodeficiency Virus-Infected Patients

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