Mechanisms of Clinically Relevant Drug Interactions Associated with Tacrolimus

Christians, Uwe; Jacobsen, Wolfgang; Benet, Leslie Z.; Lampen, Alfonso

doi:10.2165/00003088-200241110-00003

Cited by 282 publications

(241 citation statements)

References 292 publications

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“…Drugs metabolized by CYP3A4/5 inhibited tacrolimus metabolism, with ketoconazole being the most potent. Ketoconazole, cyclosporine A, diltiazem, erythromycin, and fluconazole were reported as the drugs that elicit clinically relevant drug interactions with tacrolimus (Christians et al, 2002). These results indicate the potential for metabolic interactions between tacrolimus and co-medicated drugs metabolized by CYP3A4/5.…”

Section: Wwwintechopencom Understanding the Complexities Of Kidney mentioning

confidence: 81%

“…In clinical studies, CYP3A/P-glycoprotein inhibitors and inducers primarily affect the oral bioavailability of tacrolimus rather than clearance, indicating a key role of intestinal P-glycoprotein and CYP3A. Drugs that interact with P-gp may change the distribution of tacrolimus in tissue and modify its toxicity and immunosuppressive activity (Christians et al, 2002). Ketoconazole, an azole antifungal agent, is known to be a potent inhibitor of P-gp and CYP3A4 and have even been used to reduce the dose of tacrolimus and thus save money.…”

Section: Pharmacokinetic Variability 231 Oral Bioavailabilitymentioning

confidence: 99%

“…Possible reasons include stabilization of the patient with reduction of postsurgical stress, hematocrit, ischemia-reperfusion injury and stabilization of transplant organ function, especially if the latter directly affects tacrolimus pharmacokinetics such as the liver. Also, immunosuppressive drugs affect expression and activity of CYP3A enzymes and P-gp (Christians et al, 2002). There is evidence that induction of CYP3A and P-gp by corticosteroids is responsible for the requirement to reduce tacrolimus doses as corticosteroid doses are tapered (Hesselink et al, 2003;Plosker & Foster 2000;).…”

Section: Time After Initiation Of Treatmentmentioning

confidence: 99%

See 2 more Smart Citations

Clinical Pharmacokinetics of Triple Immunosuppression Scheme in Kidney Transplant (Tacrolimus, Mycophenolate Mofetil and Corticosteroids)

Luisa¹,

Alejandro²

2011

Understanding the Complexities of Kidney Transplantation

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Section: Wwwintechopencom Understanding the Complexities Of Kidney mentioning

confidence: 81%

Section: Pharmacokinetic Variability 231 Oral Bioavailabilitymentioning

confidence: 99%

Section: Time After Initiation Of Treatmentmentioning

confidence: 99%

See 1 more Smart Citation

Clinical Pharmacokinetics of Triple Immunosuppression Scheme in Kidney Transplant (Tacrolimus, Mycophenolate Mofetil and Corticosteroids)

Luisa¹,

Alejandro²

2011

Understanding the Complexities of Kidney Transplantation

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“…Both one-and two-compartment models with or without a lag time and first-order absorption and elimination were compared in this study [20][21][22]. Typical value of the absorption rate constant (Ka) could not be estimated because of the lack of concentration data in absorption and distribution phase.…”

Section: Structural Model Buildingmentioning

confidence: 99%

Population Pharmacokinetic Analysis of Oral Tacrolimus in Patients with Glomerulonephritis

Shim¹,

Kim²,

Choi³

et al. 2016

Int J Clin Pharmacol Pharmacother

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Objective: Tacrolimus as an immunosuppressant is used to treat for several types of glomerulonephritis. Narrow therapeutic window and huge interindividual variability of tacrolimus make it impossible to predict its serum level. Hence, the purpose of this study was to derive population pharmacokinetic model for tacrolimus in glomerulonephritis patients. Materials and methods: Adult patients diagnosed with glomerulonephritis and treated with oral tacrolimus were included. Electronic medical records were reviewed retrospectively to access clinical findings and demographic data. Population pharmacokinetics of tacrolimus was evaluated using nonlinear mixed effect model by first-order conditional estimation with interaction algorithm. Results: One hundred and forty-five patients were included in this study and one thousand and nine hundreds thirty-eight blood samples were analyzed. The estimated apparent clearance (CL/F) was 19.5 L/h, and apparent volume of distribution (V/F) was 380 L. The final model suggested that serum creatinine levels were negatively correlated with both CL/F and V/F whereas serum albumin levels were positively associated with V/F. Conclusion: Various factors affecting tacrolimus pharmacokinetics were explored. The findings of this study pointed out that tacrolimus pharmacokinetics were related to patients' kidney function and serum albumin level in glomerulonephritis patients. Developed model may guide individualized tacrolimus therapy in glomerulonephritis patients and improve therapeutic outcomes in glomerulonephritis patients.

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“…In addition, the correlation between tacrolimus doses and blood concentrations is poor and pharmacokinetics is variable 14,15 . Therapeutic drug monitoring to guide tacrolimus dosing in transplant patients is therefore general clinical practice [16][17][18][19][20] .…”

Section: Introductionmentioning

confidence: 99%

Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS

Shokati

Bodenberger

Gadpaille

et al. 2015

JoVE

Self Cite

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The calcineurin inhibitor tacrolimus is the cornerstone of most immunosuppressive treatment protocols after solid organ transplantation in the United States. Tacrolimus is a narrow therapeutic index drug and as such requires therapeutic drug monitoring and dose adjustment based on its whole blood trough concentrations. To facilitate home therapeutic drug and adherence monitoring, the collection of dried blood spots is an attractive concept. After a finger stick, the patient collects a blood drop on filter paper at home. After the blood is dried, it is mailed to the analytical laboratory where tacrolimus is quantified using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) in combination with a simple manual protein precipitation step and online column extraction.For tacrolimus analysis, a 6-mm disc is punched from the saturated center of the blood spot. The blood spot is homogenized using a bullet blender and then proteins are precipitated with methanol/0.2 M ZnSO 4 containing the internal standard D 2, 13 C-tacrolimus. After vortexing and centrifugation, 100 µl of supernatant is injected into an online extraction column and washed with 5 ml/min of 0.1 formic acid/acetonitrile (7:3, v:v) for 1 min. Hereafter, the switching valve is activated and the analytes are back-flushed onto the analytical column (and separated using a 0.1% formic acid/acetonitrile gradient). Tacrolimus is quantified in the positive multi reaction mode (MRM) using a tandem mass spectrometer.The assay is linear from 1 to 50 ng/ml. Inter-assay variability (3.6%-6.1%) and accuracy (91.7%-101.6%) as assessed over 20 days meet acceptance criteria. Average extraction recovery is 95.5%. There are no relevant carry-over, matrix interferences and matrix effects. Tacrolimus is stable in dried blood spots at RT and at +4 °C for 1 week. Extracted samples in the autosampler are stable at +4 °C for at least 72 hr. Video LinkThe video component of this article can be found at

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Mechanisms of Clinically Relevant Drug Interactions Associated with Tacrolimus

Cited by 282 publications

References 292 publications

Clinical Pharmacokinetics of Triple Immunosuppression Scheme in Kidney Transplant (Tacrolimus, Mycophenolate Mofetil and Corticosteroids)

Clinical Pharmacokinetics of Triple Immunosuppression Scheme in Kidney Transplant (Tacrolimus, Mycophenolate Mofetil and Corticosteroids)

Population Pharmacokinetic Analysis of Oral Tacrolimus in Patients with Glomerulonephritis

Quantification of the Immunosuppressant Tacrolimus on Dried Blood Spots Using LC-MS/MS

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