the Drug Monitor - Drug-Drug Interactions

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Antiinfectives

General Rx

Drug Interactions Involving Immunosuppressive Agents (See: Anaizi N. Drug Interactions Involving Immunosuppressive Agents. Graft 2001; 4:232-247} [CSA = cyclosporine A; CYP3A4 = Cytochrome P450 3A4 isoform] denotes important interactions that should be prevented or require close monitoring.
Drug	Effects and Mechanisms of Interaction

Acetazolamide	PD interaction: hyperchloremic metabolic acidosis
ACE Inhibitors	PD interactions: hyperkalemia and reduced GFR (use with caution)
Acyclovir	PD interaction: increased risk of nephrotoxicity Increased risk of neurotoxicity (with CSA or tacrolimus)
Amikacin	See Nephrotoxic Drugs
Amiloride	Þ¯ renal K⁺ secretion Þ hyperkalemia
Amiodarone	See CYP3A4 inhibitors
Amphotericin B	See Nephrotoxic Drugs
Antacids	Þ ¯ absorption of immunosuppressants (particularly mycophenolate)
Anticonvulsants	See CYP3A4 inducers
Atorvastatin	See Statins
ß-blockers (Pei '93)	Þ Ý efflux of cell K⁺ Þ Ý hyperkalemia (demonstrated with CSA + ß-blockers)
Bromocriptine	See CYP3A4 inhibitors
Carbamazepine	Þ CYP3A4 induction Þ Ý metabolism (CSA, Tacro, Siro) Þ ¯ level
Captopril	See ACE Inhibitors
Carvedilol [Kaijser '97]	Þ small reduction in CSA clearance leading to a 20% dose reduction. Carvedilol is metabolized primarily by 2D6 and 2C9 with only a minor contribution by 3A4. See also ß-blockers above.
Cerivastatin	See Statins
Chloroquine	See CYP3A4 inhibitors
Cholestyramine	Þ ¯ drug absorption
Chloramphenicol (Paterson '97; Schulman '98)	See CYP3A4 inhibitors
Cimetidine	See CYP3A4 inhibitors (cimetidine is a nonspecific inhibitor of the P450)
Ciprofloxacin	PD interaction with CSA. Cipro may reduce the inhibitory effect of CSA on IL-2 production reducing the immunosuppressive effect. No evidence of PK interaction with CSA, tacrolimus, or sirolimus.
Cisapride	Þ Ý GI motility and gastric emptying Þ Ý absorption rate Þ Ý level
Clarithromycin	See CYP3A4 inhibitors
Clindamycin [Thurnheer '99]	Þ Ý clearance of CSA Þ ¯ level [minor interaction; monitor]

Clotrimazole	See CYP3A4 inhibitors
Colchicine	Þ competitive inhibition of P-GP Þ Ý penetration of CSA (tacrolimus?) through the blood brain barrier Þ Ý neurotoxicity CSA inhibits colchicine transport into bile Þ Ý colchicine level Þ acute myopathy. Use with caution.
Co-trimoxazole (Maki '92)	May exacerbate the hyperkalemia induced by tacrolimus or CSA May exacerbate the neutropenia induced by mycophenolate, azathioprine, or ganciclovir
Cyclosporine	Þ Ý bioavailability of sirolimus (possibly due to P-GP inhibition and competition for CYP3A4). Bioavailability is up 30-40% when the two drugs are separated by 4 hrs and >100% when administered together at the same time.

CYP3A4 inducers	ÞÝ expression of CYP450 ÞÝ 3A4 enzyme activity Þ Ý oxidative metabolism Þ ¯ bioavailability & Ý clearance Þ¯ blood level of immunosuppressant Þ Ý risk of acute allograft rejection. Affected immunosuppressants: CSA, tacrolimus, and sirolimus.
CYP3A4 inhibitors	Þ ¯ metabolism Þ Ý bioavailability + ¯ clearance Þ Ý blood level of CSA, tacrolimus, and sirolimus Þ Ý risk of toxicity (nephrotoxicity, neurotoxicity, myelosuppression, etc) and excessive immunosuppression (Þ infections and posttransplant lymphoproliferative disorders)..
Dexamethasone	See CYP3A4 inducers
Digoxin	CSA may inhibit the renal excretion of digoxin (via the P-GP) Þ Ý digoxin level PD interaction (cardiac digoxin toxicity) is possible due to tacrolimus-induced hyperkalemia and hypomagnesemia Digoxin may increase CSA bioavailability by 15 - 20% [Lill'00]
Danazol (Mignat '97)	See CYP3A4 inhibitors
Dapsone (Paterson '97)	See CYP3A4 inhibitors (minor interaction)
Diltiazem	See CYP3A4 inhibitors

Efavirenz	See CYP3A4 inducers
Enalapril	See ACE Inhibitors
Ergotamine (Christians '96)	See CYP3A4 inhibitors (minor interaction)
Erythromycin	See CYP3A4 inhibitors
Fluconazole	See CYP3A4 inhibitors
Fluoxetine	See CYP3A4 inhibitors
Fluvoxamine	See CYP3A4 inhibitors
Foscarnet	See Nephrotoxic Drugs
Fosinopril	See ACE Inhibitors
Fosphenytoin	See CYP3A4 inducers
Ganciclovir	PD interaction: Ý risk of nephrotoxicity (with CSA or tacrolimus) PD interaction: Ý risk of myelosuppression (azathioprine, MMF, or sirolimus)
Gentamicin	See Nephrotoxic Drugs
Grapefruit Juice	See CYP3A4 inhibitors

Hypericum perforatum (St. John's wort)	See CYP3A4 inducers (chronic use)
Itraconazole	See CYP3A4 inhibitors
Ketoconazole	See CYP3A4 inhibitors
Lovastatin	See Statins
Mefloquine (Paterson '97)	See CYP3A4 inhibitors (minor interaction)
Methylprednisolone	PD interaction: Ý immunosuppression Tacrolimus reduces steroid metabolism (steroid-sparing effect of tacrolimus)
Metoclopramide	Þ Ý GI motility and gastric emptying Þ Ý absorption rate Þ Ý peak level
Metronidazole (Herzig '99; Naderer '99)	See CYP3A4 inhibitors ¯bacterial glucuronidase Þ ¯ enterohepatic cycling of MPA Þ ¯ MPA level.
Miconazole	See CYP3A4 inhibitors
Midazolam	See CYP3A4 inhibitors
Nafcillin [Veremis'87]	Þ Ý clearance of CSA Þ ¯ level [minor interaction; monitor]
Nefazodone	See CYP3A4 inhibitors
Nelfinavir	See CYP3A4 inhibitors
Nephrotoxic Drugs	Þ Ý risk of nephrotoxicity when used with CSA or tacrolimus
Nevirapine	See CYP3A4 inducers (expected but yet to be reported)
Nicardipine	See CYP3A4 inhibitors
Nifedipine	See CYP3A4 inhibitors
NSAIDs	Þ Ý risk of nephrotoxicity
Octreotide	Þ ¯ absorption Þ ¯ level of the immunosuppressant
Omeprazole (Christians '96)	See CYP3A4 inhibitors
Oxycodone [Lill '00]	Þ ¯ CSA bioavailability by ~ 15% (mechanism unknown)
Quinidine	See CYP3A4 inhibitors (minor interaction)
Quinine [Lill '00]	Þ Ý CSA bioavailability by ~25% (mechanism unknown)
Phenobarbital	See CYP3A4 inducers
Phenytoin	See CYP3A4 inducers

Probucol [Gallego '94]	Þ ¯ CSA bioavailability Þ ¯ CSA level (mechanism unknown)
Rifabutin	See CYP3A4 inducers
Rifampin	See CYP3A4 inducers
Ritonavir	See CYP3A4 inhibitors
Rofecoxib (Vioxx^®)	See CYP3A4 inducers [Rofecoxib is not a substrate for the CYP450, but it is a mild inducer of the CYP3A4].
Saquinavir	See CYP3A4 inhibitors
Sildenafil	May competitively inhibit CYP3A4 leading to increased level of CSA, tacrolimus, and sirolimus.
Simvastatin	See Statins
Sirolimus	Þ Ý CSA bioavailability by ~15% (when separated by 4 hrs)

St John Wort	See CYP3A4 inducers (chronic use)
Statins	Atorvastatin, cerivastatin, lovastatin, and simvastatin are all substrates for 3A4 and most of them are subject to extensive pre-systemic drug metabolism. CSA (and perhaps tacrolimus) Þ Ý bioavailability & ¯ clearance of statins Þ accumulation of statins Þ Ý risk of myopathy and rhabdomyolysis Use lower doses of the statin and monitor for signs of myopathy. Separate the administration of the two drugs by at least 3 hrs.
Synercid^®	See CYP3A4 inhibitors
Spironolactone	Þ ¯ renal K⁺ secretion Þ hyperkalemia
Triamterene	Þ ¯ renal K⁺ secretion Þ hyperkalemia
Troleandomycin	See CYP3A4 inhibitors
Verapamil	See CYP3A4 inhibitors