Trimethoprim and Sulfamethoxazole are Selective Inhibitors of CYP2C8 and CYP2C9, Respectively

Abstract

ABSTRACT:To evaluate the inhibitory effects of trimethoprim and sulfamethoxazole on cytochrome P450 (P450) isoforms, selective marker reactions for CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 were examined in human liver microsomes and recombinant CYP2C8 and CYP2C9. The in vivo drug interactions of trimethoprim and sulfamethoxazole were predicted in vitro using

Reevaluation of the Microsomal Metabolism of Montelukast: Major Contribution by CYP2C8 at Clinically Relevant Concentrations

“…This conclusion is based principally on the following findings. The CYP2C8 inhibitors gemfibrozil 1-O-␤ glucuronide (Ogilvie et al, 2006) and trimethoprim (Wen et al, 2002) inhibited M6 formation from 0.05 M montelukast much more potently than did the CYP2C9 inhibitor sulfaphenazole. Recombinant CYP2C8 mediated M6 formation at an approximately 6 times higher CL int, in vitro than did CYP2C9.…”

“…Competitive inhibitors tested were trimethoprim (100 M), sulfaphenazole (10 M), omeprazole (10 M), quinidine (10 M), and ketoconazole (1 M) as inhibitors of CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively (Baldwin et al, 1995;Newton et al, 1995;Bourrié et al, 1996;Ko et al, 1997;Eagling et al, 1998;Wen et al, 2002). Mechanism-based inhibitors (MBIs) examined were furafylline (20 M), 8-methoxypsoralen (0.5 M), clopidogrel (1 M), gemfibrozil 1-O-␤ glucuronide (60 M), DDC (100 M), and troleandomycin (100 M) as inhibitors of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2E1, and CYP3A4, respectively (Newton et al, 1995;Bourrié et al, 1996;Draper et al, 1997;Koenigs et al, 1997;Eagling et al, 1998;Richter et al, 2004;Ogilvie et al, 2006).…”

Considerations when prescribing trimethoprim-sulfamethoxazole

“…Consequently, drugs metabolized by cytochrome P450 2C8 or 2C9 can accumulate during treatment with trimethoprim-sulfamethoxazole. 22 Whereas several interactions are theoretically possible under this mechanism, two merit particular emphasis: oral hypoglycemic agents and warfarin.…”

“…• Inhibition of the cytochrome P450 system (2C8 and 2C9) 22 • Renal drug transporter inhibition (organic cation transporter and organic anion transporter) 23,24 Polypharmacy Common S Sugar Hypoglycemia [25][26][27][28][29][30] • Renal insufficiency 25 • High-dose trimethoprimsulfamethoxazole 25 • Concomitant use of sulphonylureas or meglitinides [26][27][28][29][30] Common as a drug-drug interaction; rare when trimethoprimsulfamethoxazole is used in isolation Common Hyperkalemia [31][32][33][34][35][36][37] • Renal insufficiency 34,35 • High-dose trimethoprimsulfamethoxazole 32,35 • Older age 34 • Diabetes 34 • AIDS 39 • Concomitant use of ACE inhibitors, angiotensin receptor blockers, spironolactone or NSAIDs 36,37 Acute interstitial nephritis 15 …”

Elevated clozapine plasma concentration secondary to a urinary tract infection: proposed mechanisms

“…Interestingly, there was a modest increase in the clozapine/ norclozapine metabolic ratio after treatment for the UTI, which is consistent with the inhibitory effect of cotrimoxazole on CYP2C9, an enzyme involved in the demethylation of clozapine to norclozapine. 14 A second mechanism that has been proposed to explain the UTI-associated elevations in the plasma concentrations of clozapine and norclozapine is related to an increase in α1-acid glycoprotein, 10 an acute-phase protein whose synthesis is upregulated by cytokines such as IL-6. 15 An increase in α1-acid glycoprotein will increase the binding capacity of both clozapine and norclozapine.…”