Pharmacokinetic and Pharmacodynamic Properties of Indole-3-carbinol in Experimental Focal Ischemic Injury.

Abstract

Indole-3-carbinol (I3C) is reported to have neuroprotective properties in an animal model of ischemic stroke. However, the pharmacokinetics of I3C in stroke animals are unknown. Furthermore, the most effective method of I3C delivery for the treatment of stroke has yet to be determined.Therefore, the objective of this study was to evaluatepharmacokinetics and pharmacodynamicsof I3C to discover the most effective delivery route for protecting the brain from ischemic injury. With oral and intravenous administration, the pharmacokinetics and pharmacodynamics of I3C in sham and middle cerebral artery occluded (MCAO) rats were investigated. I3C administration in sham and MCAO rats did not alter the pharmacokinetic parameters such as maximum plasma concentration (Cmax), time to reach Cmax, half-life, area under the curve, mean residential time, volume of distribution, clearance, bioavailability, and tissue distribution. A higher amount of diindolylmethane (DIM) was observed with oral administration of I3C compared to intravenous administration in the plasma (5 fold), brain (4 fold), and cerebrospinal fluid (CSF) (2-3 fold). Orally delivered I3C significantly reduced neurological deficits, brain infarction (20%), blood-brain barrier leakage (15 μg/g), and brain water content (75%) in MCAO rats compared to intravenous administration of I3C. I3C pharmacokinetic parameters were similar in sham and MCAO rats, but I3C and DIM penetration in the brain and CSF was significantly higher in MCAO rats than in sham animals, and I3C oral intake significantly reduced MCAO-induced neurological impairments. Consequently, compared to intravenous treatment, I3C oral delivery is more effective in treating ischemic stroke.