Low Cyclosporin A Blood Levels and Acute Graft Rejection in a Renal Transplant Recipient during Rifampin Treatment

Offermann, G.; Keller, Frieder; Molzahn, M

doi:10.1159/000166968

Cited by 73 publications

(27 citation statements)

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“…Reductions in midazolam AUC were approximately 60 and 95% for 50 and 750 mg of avasimibe, respectively. The induction seen with avasimibe is similar to that of other CYP3A inducers, which range from 93 to 95% for rifampin (Offermann et al, 1985), carbamazepine, and phenytoin (Kishi et al, 1997). Together with the in vitro hepatocyte data, these in vivo results suggest that avasimibe induces CYP3A4 through direct activation of PXR, consequently increasing the clearance of midazolam and decreasing bioavailability.…”

Section: Discussionsupporting

confidence: 56%

Avasimibe Induces CYP3A4 and Multiple Drug Resistance Protein 1 Gene Expression through Activation of the Pregnane X Receptor

Sahi¹,

Milad²,

Zheng³

et al. 2003

J Pharmacol Exp Ther

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In vitro and clinical studies were conducted to characterize the potential of avasimibe, an acyl-CoA/cholesterol acyltransferase inhibitor to cause drug-drug interactions. Clinically, 3-and 6-fold increases in midazolam (CYP3A4 substrate) oral clearance were observed after 50 and 750 mg of avasimibe daily for 7 days, respectively. A 40% decrease in digoxin (P-glycoprotein substrate) area under the curve was observed with 750 mg of avasimibe daily for 10 days. In vitro studies were conducted to define the mechanisms of these interactions. Induction was observed in CYP3A4 activity and immunoreactive protein (EC 50 of 200 -400 nM) in primary human hepatocytes treated with avasimibe. Rifampin treatment yielded similar results. Microarray analysis revealed avasimibe (1 M) increased CYP3A4 mRNA 20-fold, compared with a 23-fold increase with 50 M rifampin. Avasimibe induced P-glycoprotein mRNA by about 2-fold and immunoreactive protein in a dose-dependent manner. Transient transfection assays showed that avasimibe is a potent activator of the human pregnane X receptor (hPXR) and more active than rifampin on an equimolar basis. Drug-drug interaction studies for CYP3A4 using pooled human hepatic microsomes and avasimibe at various concentrations, revealed IC 50 values of 20.7, 1.6, and 3.1 M using testosterone, midazolam, and felodipine as probe substrates, respectively. Our results indicate that avasimibe causes clinically significant drug-drug interactions through direct activation of hPXR and the subsequent induction of its target genes CYP3A4 and multiple drug resistance protein 1.Avasimibe is a sulfamic acid phenyl ester that inhibits acyl-CoA/cholesterol acyltransferase (ACAT), an enzyme that catalyzes the intracellular esterification of cholesterol, thereby reducing intracellular cholesterol ester content. This class of inhibitors reduces the absorption of dietary cholesterol, the secretion of hepatic very low-density lipoproteins into the plasma, and the extent of atherosclerosis (Lee et al., 1996). Avasimibe is currently in clinical trials and the doses being administered to patients are between 50 to 750 mg daily. Avasimibe has been shown to reduce triglycerides at doses between 50 and 500 mg daily (Insull et al., 2001). The pharmacokinetics of avasimibe is characterized by less than proportional increases in systemic exposure with increasing dose, as measured by maximum plasma concentrations (C max ) and the plasma concentration-time area under the curve (AUC). C max values of avasimibe were approximately 0.5 and 1.5 M after multiple oral doses of 50 and 750 mg daily, respectively (Vora et al., 1997). The lack of dose proportionality was most likely due to the poor solubility of the compound. In general, a reduction in AUC after multiple dose administration is consistent with autoinduction of the metabolic pathways of a compound and/or induction of the MDR1 gene product P-glycoprotein.Enzyme induction often results in decreasing plasma drug concentrations and the attenuation of the effect of concomitan...

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Section: Discussionsupporting

confidence: 56%

Avasimibe Induces CYP3A4 and Multiple Drug Resistance Protein 1 Gene Expression through Activation of the Pregnane X Receptor

Sahi¹,

Milad²,

Zheng³

et al. 2003

J Pharmacol Exp Ther

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“…Prompt anti-TB therapy should be initiated in patients with proven or probable TB, based on epidemiology, as well as on clinical, [90][91][92][93], rifamycin-sparing treatment regimens are preferred by many physicians. If a rifamycin is used, the risk of rejection may be increased due to lowered levels of calcineurin inhibitors; consequently, levels of cyclosporine or tacrolimus should be carefully monitored and doses should be adapted (3-5-fold increase) [93].…”

Section: Treatment Of Active Tb In Transplant Recipientsmentioning

confidence: 99%

The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement

Bumbăcea

Arend

Eyüboğlu³

et al. 2012

Eur Respir J

228

261

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Tuberculosis (TB) is a possible complication of solid organ and hematopoietic stem cell transplantation. The identification of candidates for preventive chemotherapy is an effective intervention to protect transplant recipients with latent infection with Mycobacterium tuberculosis from progressing to active disease. The best available proxy for diagnosing latent infection with M. tuberculosis is the identification of an adaptive immune response by the tuberculin skin test or an interferon-c based ex vivo assay. Risk assessment in transplant recipients for the development of TB depends on, among other factors, the locally expected underlying prevalence of infection with M. tuberculosis in the target population. In areas of high prevalence, preventive chemotherapy for all transplant recipients may be justified without immunodiagnostic testing while in areas of medium and low prevalence, preventive chemotherapy should only be offered to candidates with positive M. tuberculosis-specific immune responses. The diagnosis of TB in transplant recipients can be challenging. Treatment of TB is often difficult due to substantial interactions between anti-TB drugs and immunosuppressive medications. This management guideline summarises current knowledge on the prevention, diagnosis and treatment of TB related to solid organ and hematopoietic stem cell transplantation and provides an expert consensus on questions where scientific evidence is still lacking. KEYWORDS: Guideline, management, Mycobacterium tuberculosis, transplantation, tuberculosis T uberculosis (TB) is caused by the pathogenic species of the Mycobacterium tuberculosis complex. Only a minority of individuals who develop an adaptive immune response following infection with M. tuberculosis will ever develop TB, with the actual risk depending on the extent to which the host immune system provides a successful or inadequate response [1,2]. Therefore, individuals with impaired immune response, such as solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients, are more prone to develop TB than immunocompetent persons. TB in transplant recipients is more frequent compared to the general population (estimates from the last decades state 20-74 times as frequent in SOT [3,4] and twice as frequent in HSCT [5]), and more often fatal (up to 31% in SOT [6] and up to 50% in HSCT recipients [7]), thus adding effectiveness to interventions for its prevention, even in the face of difficulties, with treatment related to adverse drug events and drug-drug interactions. Active TB in transplant recipients can result from latent infection with M. tuberculosis (LTBI) in the transplant candidate or in the donor tissue, or from de novo post-transplant infection. These various scenarios prompt for targeted pre-transplant screening of both recipient and, if possible, donors to allow focused management of recipients selected for preventive intervention in the pre-and/or posttransplant period. The term ''preventive chemotherapy'' is used to denote treatmen...

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“…Centers using Rifampicin based regimen, would usually treat patients for 9 to 12 months. Rifampicin induces hepatic microsomal enzyme systems thereby increasing the clearance of Calcineurin inhibitors (CNI) [44], mTOR inhibitors (mTORi) [45,46], steroids and Mycophenolate [47] reducing their bioavailability and efficacy, resulting in increased risk of acute rejection and graft loss [48]. The dose of immunosuppressants has to be adjusted with TDM to maintain their levels within therapeutic range.…”

Section: Mycobacterium Tuberculosismentioning

confidence: 99%

Infections After Kidney Transplantation: The Bug Bear Of Kidney Transplantation In Tropics

Basu¹

2015

TOUNJ

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Abstract:Infections are the bugbear of kidney transplantation in the tropics, being responsible for majority of the deaths. Despite the several challenges posed by infections in kidney transplant recipient in the tropics, various developments have resulted in a decline in the rate of infections as well as their consequences. This review aims to be a basic overview of the common infections in KTR with an attempt to provide a unique tropical country perspective.

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Low Cyclosporin A Blood Levels and Acute Graft Rejection in a Renal Transplant Recipient during Rifampin Treatment

Cited by 73 publications

References 4 publications

Avasimibe Induces CYP3A4 and Multiple Drug Resistance Protein 1 Gene Expression through Activation of the Pregnane X Receptor

Avasimibe Induces CYP3A4 and Multiple Drug Resistance Protein 1 Gene Expression through Activation of the Pregnane X Receptor

The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement

Infections After Kidney Transplantation: The Bug Bear Of Kidney Transplantation In Tropics

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