Biopharm Drug Dispos. 2013 Aug 8;
Masubuchi Y, Kawaguchi Y
Drug-drug interactions associated with selective serotonin reuptake inhibitors (SSRIs) are widely known. A major interaction by SSRIs is inhibition of cytochrome P450 (P450)-mediated hepatic drug metabolism. The SSRI sertraline is also reported to increase the blood concentration of co-administered drugs. The potency of sertraline to directly inhibit hepatic drug metabolism is relatively weak as compared with the other SSRIs, implying that additional mechanisms are involved in the interactions. We examined if sertraline produces time-dependent inhibition of CYP3A4 and/or other P450 enzymes. Incubation of human liver microsomes with sertraline in the presence of NADPH resulted in marked decreases in testosterone 6?-hydroxylation activities, indicating that sertraline metabolism leads to CYP3A4 inactivation. This inactivation required NADPH and was not protected by glutathione. No significant inactivation was observed for other P450 enzymes. Spectroscopic evaluation revealed that microsomes with and without sertraline in the presence of NADPH gave a Soret peak at 455 nm, suggesting formation of metabolic intermediate (MI) complexes of sertraline metabolite(s) with reduced form of P450. This is the first report indicating that sertraline produced time-dependent inhibition of CYP3A4, which may be associated with the MI complex formation. This article is protected by copyright. All rights reserved.
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Masubuchi Y, Kawaguchi Y
Drug-drug interactions associated with selective serotonin reuptake inhibitors (SSRIs) are widely known. A major interaction by SSRIs is inhibition of cytochrome P450 (P450)-mediated hepatic drug metabolism. The SSRI sertraline is also reported to increase the blood concentration of co-administered drugs. The potency of sertraline to directly inhibit hepatic drug metabolism is relatively weak as compared with the other SSRIs, implying that additional mechanisms are involved in the interactions. We examined if sertraline produces time-dependent inhibition of CYP3A4 and/or other P450 enzymes. Incubation of human liver microsomes with sertraline in the presence of NADPH resulted in marked decreases in testosterone 6?-hydroxylation activities, indicating that sertraline metabolism leads to CYP3A4 inactivation. This inactivation required NADPH and was not protected by glutathione. No significant inactivation was observed for other P450 enzymes. Spectroscopic evaluation revealed that microsomes with and without sertraline in the presence of NADPH gave a Soret peak at 455 nm, suggesting formation of metabolic intermediate (MI) complexes of sertraline metabolite(s) with reduced form of P450. This is the first report indicating that sertraline produced time-dependent inhibition of CYP3A4, which may be associated with the MI complex formation. This article is protected by copyright. All rights reserved.
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