IDOJEH, AGHOGHO GOODLUCK

Artemether/Lumefantrine (AL) is one of the most widely used artemisinin- based combination therapies (ACTs) for the treatment of uncomplicated malaria. Given its extensive use in Nigeria and globally, a proper understanding of its drug-drug interaction potential is essential. A key mechanism underlying such interactions is the regulation of hepatic Cytochrome P450 (CYP450) enzymes. However, there is a pharmacological paradox: artemisinin derivatives such as artemether are often reported as enzyme inducers, whereas lumefantrine has been associated with inhibitory effects. It remains unclear what net effect the AL combination exerts on CYP450 expression, and this knowledge is critical for predicting clinical outcomes. Aim: The aim of this study was to examine the potential inductive or inhibitory action of AL on hepatic CYP450 enzymes in albino rats. Methods: Twenty-four albino rats were randomly divided into four groups (n=6): Group A (Olive oil vehicle control), Group B (Cimetidine inhibition control), Group C (Phenobarbital induction control), and Group D (AL test group). Treatments were administered orally once daily for 14 days, with AL given twice daily to reflect its clinical regimen. On day 15, animals were sacrificed and livers harvested for microsomal preparation. Microsomal protein concentration was determined using the Modified Lowry method, while total CYP450 content was quantified spectrophotometrically using the reduced carbon monoxide (CO) difference method. Results: The normalized CYP450 content (nmol/mg protein) of AL (0.165 ± 0.020) was not significantly different from the olive oil control (0.204 ± 0.022) but was significantly lower than cimetidine (0.451 ± 0.069) and phenobarbital (0.717 ± 0.186). This indicates that the expected substrate-driven induction was nullified in the AL group, aligning its CYP450 content with the inhibitory baseline. There was no significant difference in the percentage weight change between the AL group (20.10 ± 1.85) and the control group (14.20 ± 4.18). Supporting parameters such as protein concentration (16.87 ± 2.20) and denatured protein (37.70 ± 0.03) confirms that AL’s effect was specific to CYP450 modulation and not due to systemic toxicity. Conclusion: This study shows that Artemether/Lumefantrine (AL) is a net hepatic CYP450 enzyme inhibitor in albino rats. Clinically, AL may slow the metabolism of co- administered drugs, increasing the risk of accumulation and toxicity in polypharmacy cases common in malaria-endemic regions. This highlights the need for careful monitoring and possible dose adjustments of concomitant medications.