Use of Enantiomeric Bupropion and Hydroxybupropion to Assess CYP2B6 Activity in Glomerular Kidney Diseases

Abstract

Chronic kidney disease affects more than 50 million people in the U.S.1. The top three etiologies for end-stage kidney disease are diabetes mellitus (45% of patients), hypertension (29% of patients), and glomerulonephritis (19% of patients).2 While it is well established that chronic kidney diseases can result in decreased elimination of drugs via the kidneys, the effects of kidney disease on non-renal clearance processes, especially specific metabolic routes, are less well described. Experimental models of chronic kidney disease have reported reductions in hepatic cytochrome P450 (CYP) enzymes including 3A1, 3A2, 2C11, and N-acetyltransferases.3–5 Reductions in nonrenal clearance ranging from 30% to 67% have been reported for substrates of the CYP3A4, CYP2D6, CYP2B6, and CYP2C9 enzymes in patients with kidney disease.6 In order to fully understand the clinical significance of altered metabolic routes associated with kidney disease, it will be necessary to evaluate the effects that specific forms of kidney diseases have on these pathways and whether these processes effect drug disposition. Numerous studies have reported various probe drugs or cocktail approaches to evaluate the in vivo function of various drug metabolizing enzymes and transporters in patients.7, 8 However, only a few studies9–12 were actually conducted in chronic kidney disease patients, and hence applicability of most of the published studies beyond the healthy control population remains to be established. As chronic kidney disease patients are commonly prescribed ~10–12 different daily medications13, studies that evaluate metabolic pathway alterations should address requirements for modifications in drug regimens as well as drug interaction potential. While studies designed to assess and report the pharmacokinetics of bupropion exist14, 15, studies designed specifically to assess the influence of chronic kidney diseases on CYP2B6 activity are currently nonexistent. CYP2B6 is responsible for the metabolism of 3–8% of the currently marketed drugs16, 17 including bupropion, cyclophosphamide, efavirenz, selegiline, methadone, and sertraline18–22 and several drugs, including clopidrogrel, ticlopidine, clotrimazole, itraconazole, sertraline, and raloxifene have been purported to inhibit CYP2B6.23 Data from healthy subjects demonstrate that both the R and S enantiomers of bupropion and its hydroxy-metabolite are present in plasma, but only stereoselective S bupropion and (S,S) hydroxybupropion formation clearance have been shown to be a phenotypic probe for CYP2B624, complicating the assessment of in vivo activity. The purpose of the current study was to evaluate the pharmacokinetics of enantiomeric bupropion and its hydroxybupropion metabolite in patients with kidney diseases affecting the glomerulus in order to provide an assessment of CYP2B6 activity in this disease state.