Solid Organ Transplantation Pharmacogenomics and Drug-Drug Interactions Quiz

Solid Organ Transplantation Pharmacogenomics and Drug-Drug Interactions

• Pharmacogenetics and pharmacogenomics are the study of how genetic variations affect drug response and toxicity.

• Variability in pharmacokinetics of immunosuppressants can be caused by patient factors, genetic polymorphisms, and drug-drug interactions.

• CYP3A5, CYP3A4, and P-glycoprotein are enzymes and transporters that contribute to the metabolism of tacrolimus, cyclosporine, and sirolimus and exhibit genetic polymorphisms.

• The MDR1 gene encodes P-glycoprotein, which is an ATP-driven efflux pump that can impact drug disposition.

• An SNP in intron 3 of the CYP3A5 gene causes a splicing error and aberrantly spliced mRNA with a premature stop codon, resulting in significantly reduced enzyme expression.

• CYP3A5 may represent up to 50% of the total hepatic CYP3A content in people who are CYP3A5*1/3 or CYP3A51/*1, and may contribute to inter-individual and inter-racial differences in CYP3A-dependent drug clearance.

• Mycophenolic acid (MPA) has several UGTs that metabolize it, and two SNPs in UGT1A9 have been associated with lower overall exposure to MPA.

• The activity of MPA is derived from its inhibition of inosine monophosphate dehydrogenase (IMPDH), and reports suggest that IMPDH polymorphisms could play a part in the activity of MPA.

• CNI-mediated nephrotoxicity may be due to intrarenal accumulation of the parent drug, but conversion of parent drug to metabolite can serve as a protective mechanism from damage to the kidney.

• Prospective genotyping for CYP3A5 may be beneficial for initial dose selection of tacrolimus and sirolimus, and may help predict the risk of CNI-induced nephrotoxicity.

• CYP3A5 genotyping might also be of some clinical value in predicting the risk of CNI-induced nephrotoxicity and in medication selection for patients with a higher risk for renal dysfunction.

• Drug-drug interactions can affect the blood concentrations of cyclosporine, tacrolimus, sirolimus, and everolimus, and substances that inhibit CYP3A4/5 can increase drug concentrations, while drugs that induce CYP3A activity can decrease drug concentrations.Drug Interactions in Solid-Organ Transplantation

• Sirolimus and CNIs require separate administration times to avoid interactions.

• Sirolimus exacerbates CNI-induced renal dysfunction, while CNIs increase sirolimus-induced hyperlipidemia and myelosuppression.

• Co-administration of CNIs with NSAIDs and other renal-dysfunction-inducing drugs can cause additive nephrotoxicity.

• CNIs can elevate methotrexate levels and reduce clearance of drugs like prednisolone, digoxin, and statins.

• Co-administration of cyclosporine and ketoconazole can significantly elevate blood levels of cyclosporine, requiring a decrease in dosage regimen.

• The interaction between cyclosporine and ketoconazole can lead to savings of nearly $5,000/year per transplant recipient.

• Antacids, cholestyramine, and calcium polycarbophil can reduce blood levels of Cellcept® and Myfortic® significantly.

• Xanthine oxidase, blocked by allopurinol, is of major importance in the metabolism of azathioprine metabolites, and the combination of azathioprine with allopurinol should be avoided.

• Adverse effects resulting from co-administration of azathioprine with other myelosuppressive agents or angiotensin-converting enzyme inhibitors include leukopenia, thrombocytopenia, and anemia as a result of myelosuppression.

• Barbiturates, phenytoin, and rifampin induce hepatic metabolism of prednisone, decreasing its effectiveness.

• Prednisone decreases the effectiveness of vaccines and toxoids.

• For questions, contact [email protected].

Solid Organ Transplantation Pharmacogenomics and Drug-Drug Interactions

• Pharmacogenetics and pharmacogenomics are the study of how genetic variations affect drug response and toxicity.

• Variability in pharmacokinetics of immunosuppressants can be caused by patient factors, genetic polymorphisms, and drug-drug interactions.

• CYP3A5, CYP3A4, and P-glycoprotein are enzymes and transporters that contribute to the metabolism of tacrolimus, cyclosporine, and sirolimus and exhibit genetic polymorphisms.

• The MDR1 gene encodes P-glycoprotein, which is an ATP-driven efflux pump that can impact drug disposition.

• An SNP in intron 3 of the CYP3A5 gene causes a splicing error and aberrantly spliced mRNA with a premature stop codon, resulting in significantly reduced enzyme expression.

• CYP3A5 may represent up to 50% of the total hepatic CYP3A content in people who are CYP3A5*1/3 or CYP3A51/*1, and may contribute to inter-individual and inter-racial differences in CYP3A-dependent drug clearance.

• Mycophenolic acid (MPA) has several UGTs that metabolize it, and two SNPs in UGT1A9 have been associated with lower overall exposure to MPA.

• The activity of MPA is derived from its inhibition of inosine monophosphate dehydrogenase (IMPDH), and reports suggest that IMPDH polymorphisms could play a part in the activity of MPA.

• CNI-mediated nephrotoxicity may be due to intrarenal accumulation of the parent drug, but conversion of parent drug to metabolite can serve as a protective mechanism from damage to the kidney.

• Prospective genotyping for CYP3A5 may be beneficial for initial dose selection of tacrolimus and sirolimus, and may help predict the risk of CNI-induced nephrotoxicity.

• CYP3A5 genotyping might also be of some clinical value in predicting the risk of CNI-induced nephrotoxicity and in medication selection for patients with a higher risk for renal dysfunction.

• Drug-drug interactions can affect the blood concentrations of cyclosporine, tacrolimus, sirolimus, and everolimus, and substances that inhibit CYP3A4/5 can increase drug concentrations, while drugs that induce CYP3A activity can decrease drug concentrations.Drug Interactions in Solid-Organ Transplantation

• Sirolimus and CNIs require separate administration times to avoid interactions.

• Sirolimus exacerbates CNI-induced renal dysfunction, while CNIs increase sirolimus-induced hyperlipidemia and myelosuppression.

• Co-administration of CNIs with NSAIDs and other renal-dysfunction-inducing drugs can cause additive nephrotoxicity.

• CNIs can elevate methotrexate levels and reduce clearance of drugs like prednisolone, digoxin, and statins.

• Co-administration of cyclosporine and ketoconazole can significantly elevate blood levels of cyclosporine, requiring a decrease in dosage regimen.

• The interaction between cyclosporine and ketoconazole can lead to savings of nearly $5,000/year per transplant recipient.

• Antacids, cholestyramine, and calcium polycarbophil can reduce blood levels of Cellcept® and Myfortic® significantly.

• Xanthine oxidase, blocked by allopurinol, is of major importance in the metabolism of azathioprine metabolites, and the combination of azathioprine with allopurinol should be avoided.

• Adverse effects resulting from co-administration of azathioprine with other myelosuppressive agents or angiotensin-converting enzyme inhibitors include leukopenia, thrombocytopenia, and anemia as a result of myelosuppression.

• Barbiturates, phenytoin, and rifampin induce hepatic metabolism of prednisone, decreasing its effectiveness.

• Prednisone decreases the effectiveness of vaccines and toxoids.

• For questions, contact [email protected].

Solid Organ Transplantation Pharmacogenomics and Drug-Drug Interactions

• Pharmacogenetics and pharmacogenomics are the study of how genetic variations affect drug response and toxicity.

• Variability in pharmacokinetics of immunosuppressants can be caused by patient factors, genetic polymorphisms, and drug-drug interactions.

• CYP3A5, CYP3A4, and P-glycoprotein are enzymes and transporters that contribute to the metabolism of tacrolimus, cyclosporine, and sirolimus and exhibit genetic polymorphisms.

• The MDR1 gene encodes P-glycoprotein, which is an ATP-driven efflux pump that can impact drug disposition.

• An SNP in intron 3 of the CYP3A5 gene causes a splicing error and aberrantly spliced mRNA with a premature stop codon, resulting in significantly reduced enzyme expression.

• CYP3A5 may represent up to 50% of the total hepatic CYP3A content in people who are CYP3A5*1/3 or CYP3A51/*1, and may contribute to inter-individual and inter-racial differences in CYP3A-dependent drug clearance.

• Mycophenolic acid (MPA) has several UGTs that metabolize it, and two SNPs in UGT1A9 have been associated with lower overall exposure to MPA.

• The activity of MPA is derived from its inhibition of inosine monophosphate dehydrogenase (IMPDH), and reports suggest that IMPDH polymorphisms could play a part in the activity of MPA.

• CNI-mediated nephrotoxicity may be due to intrarenal accumulation of the parent drug, but conversion of parent drug to metabolite can serve as a protective mechanism from damage to the kidney.

• Prospective genotyping for CYP3A5 may be beneficial for initial dose selection of tacrolimus and sirolimus, and may help predict the risk of CNI-induced nephrotoxicity.

• CYP3A5 genotyping might also be of some clinical value in predicting the risk of CNI-induced nephrotoxicity and in medication selection for patients with a higher risk for renal dysfunction.

• Drug-drug interactions can affect the blood concentrations of cyclosporine, tacrolimus, sirolimus, and everolimus, and substances that inhibit CYP3A4/5 can increase drug concentrations, while drugs that induce CYP3A activity can decrease drug concentrations.Drug Interactions in Solid-Organ Transplantation

• Sirolimus and CNIs require separate administration times to avoid interactions.

• Sirolimus exacerbates CNI-induced renal dysfunction, while CNIs increase sirolimus-induced hyperlipidemia and myelosuppression.

• Co-administration of CNIs with NSAIDs and other renal-dysfunction-inducing drugs can cause additive nephrotoxicity.

• CNIs can elevate methotrexate levels and reduce clearance of drugs like prednisolone, digoxin, and statins.

• Co-administration of cyclosporine and ketoconazole can significantly elevate blood levels of cyclosporine, requiring a decrease in dosage regimen.

• The interaction between cyclosporine and ketoconazole can lead to savings of nearly $5,000/year per transplant recipient.

• Antacids, cholestyramine, and calcium polycarbophil can reduce blood levels of Cellcept® and Myfortic® significantly.

• Xanthine oxidase, blocked by allopurinol, is of major importance in the metabolism of azathioprine metabolites, and the combination of azathioprine with allopurinol should be avoided.

• Adverse effects resulting from co-administration of azathioprine with other myelosuppressive agents or angiotensin-converting enzyme inhibitors include leukopenia, thrombocytopenia, and anemia as a result of myelosuppression.

• Barbiturates, phenytoin, and rifampin induce hepatic metabolism of prednisone, decreasing its effectiveness.

• Prednisone decreases the effectiveness of vaccines and toxoids.

• For questions, contact [email protected].

Solid Organ Transplantation Pharmacogenomics and Drug-Drug Interactions

• Pharmacogenetics and pharmacogenomics are the study of how genetic variations affect drug response and toxicity.

• Variability in pharmacokinetics of immunosuppressants can be caused by patient factors, genetic polymorphisms, and drug-drug interactions.

• CYP3A5, CYP3A4, and P-glycoprotein are enzymes and transporters that contribute to the metabolism of tacrolimus, cyclosporine, and sirolimus and exhibit genetic polymorphisms.

• The MDR1 gene encodes P-glycoprotein, which is an ATP-driven efflux pump that can impact drug disposition.

• An SNP in intron 3 of the CYP3A5 gene causes a splicing error and aberrantly spliced mRNA with a premature stop codon, resulting in significantly reduced enzyme expression.

• CYP3A5 may represent up to 50% of the total hepatic CYP3A content in people who are CYP3A5*1/3 or CYP3A51/*1, and may contribute to inter-individual and inter-racial differences in CYP3A-dependent drug clearance.

• Mycophenolic acid (MPA) has several UGTs that metabolize it, and two SNPs in UGT1A9 have been associated with lower overall exposure to MPA.

• The activity of MPA is derived from its inhibition of inosine monophosphate dehydrogenase (IMPDH), and reports suggest that IMPDH polymorphisms could play a part in the activity of MPA.

• CNI-mediated nephrotoxicity may be due to intrarenal accumulation of the parent drug, but conversion of parent drug to metabolite can serve as a protective mechanism from damage to the kidney.

• Prospective genotyping for CYP3A5 may be beneficial for initial dose selection of tacrolimus and sirolimus, and may help predict the risk of CNI-induced nephrotoxicity.

• CYP3A5 genotyping might also be of some clinical value in predicting the risk of CNI-induced nephrotoxicity and in medication selection for patients with a higher risk for renal dysfunction.

• Drug-drug interactions can affect the blood concentrations of cyclosporine, tacrolimus, sirolimus, and everolimus, and substances that inhibit CYP3A4/5 can increase drug concentrations, while drugs that induce CYP3A activity can decrease drug concentrations.Drug Interactions in Solid-Organ Transplantation

• Sirolimus and CNIs require separate administration times to avoid interactions.

• Sirolimus exacerbates CNI-induced renal dysfunction, while CNIs increase sirolimus-induced hyperlipidemia and myelosuppression.

• Co-administration of CNIs with NSAIDs and other renal-dysfunction-inducing drugs can cause additive nephrotoxicity.

• CNIs can elevate methotrexate levels and reduce clearance of drugs like prednisolone, digoxin, and statins.

• Co-administration of cyclosporine and ketoconazole can significantly elevate blood levels of cyclosporine, requiring a decrease in dosage regimen.

• The interaction between cyclosporine and ketoconazole can lead to savings of nearly $5,000/year per transplant recipient.

• Antacids, cholestyramine, and calcium polycarbophil can reduce blood levels of Cellcept® and Myfortic® significantly.

• Xanthine oxidase, blocked by allopurinol, is of major importance in the metabolism of azathioprine metabolites, and the combination of azathioprine with allopurinol should be avoided.

• Adverse effects resulting from co-administration of azathioprine with other myelosuppressive agents or angiotensin-converting enzyme inhibitors include leukopenia, thrombocytopenia, and anemia as a result of myelosuppression.

• Barbiturates, phenytoin, and rifampin induce hepatic metabolism of prednisone, decreasing its effectiveness.

• Prednisone decreases the effectiveness of vaccines and toxoids.

• For questions, contact [email protected].