Effects of piperine–haloperidol mixture on ketamine induced schizophrenia rats and metabolism-mediated inhibitory potency: in-vivo and in-vitro evaluation

Haloperidol, a conventional antipsychotic, was mixed with piperine in a ketamine-induced schizophrenia rat model to evaluate the interaction potential of this mixture through in-vitro and in-vivo analyses. Piperine, known for its CYP450 enzyme inhibitory effects, enhances the bioavailability of various drugs. Initial in-vitro assays using a high-throughput fluorometric method showed that the haloperidol–piperine mixture inhibited CYP3A4 and CYP2D6 enzymes, comparable to positive controls. In-vivo pharmacokinetic results revealed that piperine significantly increased haloperidol’s plasma concentration and area under the curve while reducing clearance, indicating enhanced bioavailability. Pharmacodynamic assessments showed reductions in locomotor activity, immobility time, dopamine levels, and nitric oxide, with increased superoxide dismutase levels in the haloperidol–piperine group compared to haloperidol alone, reflecting enhanced therapeutic efficacy. These findings indicate that piperine can increase haloperidol exposure, potentially allowing for dose reduction and minimizing dose-related side effects. Limitations of this study include reliance on a rat model, which may not fully replicate human metabolism, and lack of long-term safety assessment. Future studies should explore the clinical applicability of this mixture in human trials, particularly focusing on safety, dosage optimization, and long-term effects. Additionally, understanding piperine’s role in different metabolic pathways could guide the development of targeted bioavailability enhancers, improving efficacy for a range of CYP450-metabolized medications.