Pharmacokinetic and Adrenal Interactions of IL‐10 and Prednisone in Healthy Volunteers

Chakraborty, Abhijit; Blum, Robert A.; Mis, Suzette M.; Cutler, David L.; Jusko, William J.

doi:10.1177/00912709922008137

Cited by 28 publications

(22 citation statements)

References 23 publications

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“…17,19 In our study, the TBW-normalized mean free prednisolone oral clearance in male subjects was significantly higher than the corresponding mean in female subjects, regardless of race (by 22% in whites, 40% in blacks; p < 0.01, Table II). The TBW-normalized apparent volume of distribution was also higher in men than in women (by 32% in whites, 38% in blacks; p < 0.01).…”

Section: Discussionmentioning

confidence: 40%

“…Using previous data, 19 a sample size of 8 per group was calculated to provide a 90%power with an alpha level of 0.05 in detecting a 25 L/h (26% of the reported mean) difference in free prednisolone oral clearance with a standard deviation of 15 L/h. The study was approved by the Kaleida Health Millard Fillmore Hospital Institutional Review Board (Buffalo, NY).…”

Section: Methods Subjectsmentioning

confidence: 99%

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Prednisolone Pharmacokinetics and Pharmacodynamics in Relation to Sex and Race

Magee

Blum

Lates

et al. 2001

The Journal of Clinical Pharma

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108

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Prednisolone pharmacokinetics (PK) and pharmacodynamics (PD) were investigated in relation to sex and race in white males, black males, white females, and black females (n = 8/group) after a single oral dose (0.27 mg/kg) of prednisone. The study consisted of baseline and prednisone phases with 32-hour sampling in each phase. Women were studied during the luteal phase of their menstrual cycle. Total and free plasma prednisolone concentrations were assayed by HPLC and ultrafiltration, and pharmacokinetic data were analyzed by compartmental fitting using WinNonlin. Plasma cortisol concentrations were assayed by HPLC; T-helper, T-suppressor lymphocyte, and neutrophil cell counts were determined by FACS and hemocytometry, and these pharmacodynamic data were evaluated by basic and extended indirect response models using ADAPT II. Total body weight-normalized free prednisolone oral clearance and apparent volume of distribution were higher in men compared with women, regardless of race (by22%in whites and40%in blacks for oral clearance, p < 0.01; by32%in whites and38% in blacks for apparent volume of distribution, p < 0.01). The 50% inhibitory concentration (IC 50 ) values for T-suppressor cell-trafficking inhibition were higher in whites than in blacks, regardless of sex (by 125% in men and 208% in women, p < 0.01). The IC 50 or SC 50 values for effects of prednisolone on cortisol secretion and T-helper lymphocyte or neutrophil trafficking were not statistically different between men and women, blacks and whites. The findings of this study suggest that there are some prednisolone PK/PD differences related to sex and race. However, these differences do not suggest the need for dosage adjustments, and additional experiments with repeat dosing are needed to fully evaluate the clinical implication of these findings.The role of sex as a factor in the pharmacokinetics and the pharmacodynamics (PK/PD) of drugs has become well appreciated. 1 Women often exhibit modestly more rapid clearances of drugs metabolized by the CYP3A4 pathway (e.g., methylprednisolone 2 ). They may also show alterations in the disposition of drugs in relation to the phase of the menstrual cycle (e.g., theophylline 3 ), pregnancy (e.g., caffeine 4 ), or after menopause (e.g., verapamil 5 ). Women receiving oral contraceptives are likely to show more rapid clearances of conjugated NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript drugs (e.g., oxazepam) but have reduced clearances of many oxidized compounds (e.g., prednisolone 6 ). Interpretation of data is sometimes complicated by the need to assess whether pharmacokinetic parameters are properly normalized for body weight differences and if the phase of the menstrual cycle was monitored.The assessment of pharmacodynamic differences between men and women requires control of pharmacokinetic factors and use of appropriate methodology to relate responses to plasma or biophase drug concentrations. There are some notable examples of marked sex differences in drug efficacy. As...

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Section: Discussionmentioning

confidence: 40%

Section: Methods Subjectsmentioning

confidence: 99%

Prednisolone Pharmacokinetics and Pharmacodynamics in Relation to Sex and Race

Magee

Blum

Lates

et al. 2001

The Journal of Clinical Pharma

Self Cite

108

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“…9 In this study, we observed a significant increase in metabolism of prednisolone to prednisone due to LPS stimulation. An earlier study indicated the role of cytokines in suppressing the induction of cytochrome P-450 isoenymes, including CYP3A4, 22 which is partly responsible for the metabolism of prednisolone.…”

Section: Discussionmentioning

confidence: 49%

“…NO Generation through TNF-α- (7) (8) (9) where PreiNOS represents the precursor to inducible nitric oxide (iNOS) enzyme, k NO,# are intercompartmental rate constants describing the production of NO from TNF-α following LPS induction, the power coefficient (δ) adjusts for transduction, and k el,NO is the first-order elimination rate constant of NO x .…”

Section: No Dynamicsmentioning

confidence: 99%

Pharmacodynamic interactions between recombinant mouse interleukin‐10 and prednisolone using a mouse endotoxemia model

Chakraborty

Yeung

Pyszczynski

et al. 2005

Journal of Pharmaceutical Sciences

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The pharmacodynamic interactions between recombinant mouse interleukin-10 (IL-10) and prednisolone were examined in lipopolysaccharide (LPS)-induced experimental endotoxemia in Balb/c mice. Treatment phases consists of single doses of IL-10 (10 μg/kg i.p.), prednisolone (25 (mg/kg i.p.), IL-10 (2.5 μg/kg i.p.) with prednisolone (6.25 mg/kg i.p.), or placebo (saline). Measurements included plasma steroid kinetics and IL-10 concentrations and responses to LPS including proinflammatory cytokines (TNF-α, IFN-γ) and circulatory NO measured as plasma nitrate/nitrite concentrations. The intraperitoneal dosing of LPS produced large and transient elevations of plasma TNF-α, IFN-γ, and NO concentrations. Noncompartmental and model fitting using extended indirect response models based on drug inhibition of multiphase stimulation of biomarkers by LPS were used to describe the in vivo pharmacodynamics and drug interactions. Dosing with prednisolone, IL-10, or their combinations produced strong inhibition of cytokine and NO production. The IC 50 values of prednisolone ranged from 54 to 171 ng/mL, and IC 50 values for IL-10 ranged from 0.06 to 0.69 ng/mL. The production of NO was described as a cascading consequence of the TNF-α and IFN-γ plasma concentrations. The joint dosing of IL-10 with prednisolone produces moderately synergistic immunosuppressive effects in this system. Both drugs were sufficiently protective in suppressing the inflammatory mediators when administered prior to the LPS trigger, while such effects were modest when administered after the inflammatory stimulus was provoked. The integrated and complex pharmacokinetic/pharmacodynamic models well capture the in vivo processes, drug potencies, and interactions of IL-10 and prednisolone.

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“…Clinical trials in which IL-10 was administrated systemically to healthy volunteers have demonstrated that, at doses associated with biological activities, this cytokine has minimal side effects [209][210][211][212][213], including a mild flu-like syndrome [210], transient mild to moderate neutrophilia, monocytosis, lymphopenia (dramatic reductions of 40-70% in circulating lymphocytes expressing the T cell markers CD2, CD3, and CD7), and a delayed decrease of platelet count [209,210]. Thus, IL-10 has been proposed as a candidate for treatment of bacterial sepsis, and more generally as an effective anti-inflammatory agent [72] and clinical trials have shown that its systemic administration is followed by modest but significant improvement of psoriasis [214,215], Crohn's disease [216], rheumatoid arthritis [217], and chronic hepatitis C infection [218].…”

Section: Il-10 Administration: Possible Implications In the Preventiomentioning

confidence: 99%

The anti-inflammatory limb of the immune response in preterm labor, intra-amniotic infection/inflammation, and spontaneous parturition at term: A role for interleukin-10

Gotsch

Romero

Kusanovic

et al. 2008

The Journal of Maternal-Fetal & Neonatal Medicine

122

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Objective. The anti-inflammatory limb of the immune response is crucial for dampening inflammation. Spontaneous parturition at term and preterm labor (PTL) are mediated by inflammation in the cervix, membranes, and myometrium. This study focuses on the changes in the amniotic fluid concentrations of the anti-inflammatory cytokine interleukin (IL)-10. The objectives of this study were to determine whether there is a relationship between amniotic fluid concentrations of IL-10 and gestational age, parturition (at term and preterm), and intra-amniotic infection/inflammation (IAI). Study design. A cross-sectional study was conducted including 301 pregnant women in the following groups: (1) midtrimester of pregnancy who delivered at term (n ¼ 112); (2) mid-trimester who delivered preterm neonates (n ¼ 30); (3) term not in labor without IAI (n ¼ 40); (4) term in labor without IAI (n ¼ 24); (5) term in labor with IAI (n ¼ 20); (6) PTL without IAI who delivered at term (n ¼ 31); (7) PTL without IAI who delivered preterm (n ¼ 30); (8) PTL with IAI who delivered preterm (n ¼ 14). IL-10 concentrations in amniotic fluid were determined by a specific and sensitive immunoassay. Nonparametric statistics were used for analysis. Results.(1) IL-10 was detectable in amniotic fluid and its median concentration did not change with gestational age from mid-trimester to term. (2) Patients in labor at term had a significantly higher median amniotic fluid IL-10 concentration than that of patients at term not in labor (p ¼ 0.04). (3) Women at term in labor with IAI had a significantly higher median amniotic fluid IL-10 concentration than that of patients at term in labor without IAI (p ¼ 0.02). (4) Women with PTL and IAI who delivered preterm had a significantly higher median amniotic fluid concentration of IL-10 than those without IAI who delivered preterm and than those who delivered at term (p ¼ 0.009 and p 5 0.001, respectively). (5) Among patients with preterm labor without IAI, those who delivered preterm had a significantly higher median amniotic fluid IL-10 concentration than those who delivered at term (p ¼ 0.03). Conclusions. The anti-inflammatory cytokine IL-10 is detectable in the amniotic fluid of normal pregnant women. Spontaneous parturition at term and in preterm gestation is associated with increased amniotic fluid concentrations of IL-10. IAI (preterm and at term) is also associated with increased amniotic fluid concentrations of IL-10. We propose that IL-10 has a role in the regulation of the immune response in vivo by initiating actions that dampen inflammation.

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Pharmacokinetic and Adrenal Interactions of IL‐10 and Prednisone in Healthy Volunteers

Cited by 28 publications

References 23 publications

Prednisolone Pharmacokinetics and Pharmacodynamics in Relation to Sex and Race

Prednisolone Pharmacokinetics and Pharmacodynamics in Relation to Sex and Race

Pharmacodynamic interactions between recombinant mouse interleukin‐10 and prednisolone using a mouse endotoxemia model

The anti-inflammatory limb of the immune response in preterm labor, intra-amniotic infection/inflammation, and spontaneous parturition at term: A role for interleukin-10

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