Safety Assessment of Spirulina Intake on Cytochrome P450 3A-Mediated Drug Metabolism: A Comprehensive Study from an In Vitro Study to a Human Clinical Trial

Spirulina has been gaining increasing attention as a dietary supplement, yet its potential to induce food–drug interactions when taken alongside medications remains insufficiently understood. Inhibition of cytochrome P450 3A (CYP3A), a major drug-metabolizing enzyme, is of concern, as it may play a key role in adverse effect development. Therefore, we aimed to determine whether spirulina induces food–drug interactions through CYP3A inhibition. To assess the inhibitory effects of spirulina on CYP3A activity, midazolam was used as a probe substrate. The inhibitory effects of spirulina and its main components were examined in vitro on midazolam 1′-hydroxylation activity in human liver microsomes. In vivo, rats received a single oral dose of spirulina powder before midazolam administration, and serum midazolam concentrations were compared with those of a control group. A clinical study was also conducted in six healthy Japanese men to examine the effects of short-term, repeated spirulina tablet intake on serum midazolam concentrations in an open-label, two-period, fixed-sequence design. The in vitro results revealed that spirulina inhibited midazolam 1′-hydroxylation activity in a concentration-dependent manner. Among its major components, phycocyanin exhibited weak inhibition, whereas chlorophyll a, zeaxanthin, and β-carotene showed no significant effects. In rats, the AUC0-∞ of midazolam tended to increase by approximately 25% following spirulina administration. However, in the clinical trial, no significant changes were observed in the AUC0-8 or Cmax of midazolam. These findings suggest that short-term spirulina intake is unlikely to cause substantial CYP3A inhibition, though further studies are warranted to fully rule out minor interactions.