Circadian sensitivity to the cardiac glycoside oleandrin is associated with diurnal intestinal P-glycoprotein expression

Toxicity of oleandrin in mice varies significantly with dosing time, showing a 2.9-fold difference in drug exposure.

• Cardiac toxicity, indicated by plasma markers CK-MB, LDH, and cTn-I, was lower at ZT10 compared to ZT2 and ZT22.
• Mice lacking Bmal1 in the intestine showed reduced levels of mdr1a mRNA and P-gp protein, disrupting their daily rhythms.
• Oleandrin is identified as a substrate for P-glycoprotein (P-gp), with overexpression of P-gp linked to decreased sensitivity to oleandrin toxicity.
• Circadian variations in P-gp levels and drug exposure suggest that timing of oleandrin dosing may influence its toxicity.
• Bmal1's regulation of mdr1a transcription involves clock output genes Hlf and E4bp4, which are crucial for maintaining rhythmic drug metabolism.

AI simplified