Albendazole metabolism in patients with neurocysticercosis: antipyrine as a multifunctional marker drug of cytochrome P450

Abstract

The present study investigates the isoform(s) of cytochrome P450 (CYP) involved in the metabolism of albendazole sulfoxide (ASOX) to albendazole sulfone (ASON) in patients with neurocysticercosis using antipyrine as a multifunctional marker drug. The study was conducted on 11 patients with neurocysticercosis treated with a multiple dose regimen of albendazole for 8 days (5 mg/kg every 8 h). On the 5th day of albendazole treatment, 500 mg antipyrine was administered po. Blood and urine samples were collected up to 72 h after antipyrine administration. Plasma concentrations of (+)-ASOX, (-)-ASOX and ASON were determined by HPLC using a chiral phase column and detection by fluorescence. The apparent clearance (CL/f) of ASON and of the (+) and (-)-ASOX enantiomers were calculated and compared to total antipyrine clearance (CL T ) and the clearance for the production of the three major antipyrine metabolites (CL m ). A correlation (P≤0.05) was obtained only between the CL T of antipyrine and the CL/f of ASON (r = 0.67). The existence of a correlation suggests the involvement of CYP isoforms common to the metabolism of antipyrine and of ASOX to ASON. Since the CL T of antipyrine is a general measure of CYP enzymes but with a slight to moderate weight toward CYP1A2, we suggest the involvement of this enzyme in ASOX to ASON metabolism in man. The study supports the establishment of a specific marker drug of CYP1A2 in the study of the in vivo metabolism of ASOX to ASON.

The Cytochrome P450 Superfamily: Biochemistry, Evolution and Drug Metabolism in Humans

“…In addition to its role in the bioactivation of carcinogens, CYP1A2 also plays a minor role in the metabolism of numerous pharmaceuticals including antipyrine [147], mexiletine [148], granisetron [149], melatonin [150], phenacetin [151], theophylline [152] and warfarin [153]. CYP1A2, has also been shown to oxidize uroporphyrinogen to uroporphyrin in the course of heme metabolism and to hydroxylate estrogen.…”

Therapy for neurocysticercosis

“…First, there is considerable inter-individual variability in the plasma concentration of PZQ and ASOX [26,52,53]. The exact mechanism of this variability in the plasma concentration of the drug is not clear but may include a gender factor -greater ASOX concentration in women than in men -and dominant expression of cytochrome P450 isoforms [54,55].…”

“…Considering that multiple drug therapy is a common therapeutic practice in patients with NCC, careful evaluation of drug interactions is essential to understand the actual effectiveness of anticysticercal drugs [55]. On the basis of the high inter-individual variability and the complex pharmacological interactions, monitoring of plasma concentration of PZQ and ASOX would be highly recommended in patients receiving anticysticercal therapy.…”

Routine drug and food interactions during antihelminthic treatment of neurocysticercosis: A reason for the variable efficacy of albendazole and praziquantel?

“…Flavin‐containing monooxygenases and cytochrome P450 (CYP) 3A isoenzymes are responsible for the first pass hepatic metabolism of albendazole into albendazole sulfoxide . Albendazole sulfoxide is then converted into an inactive metabolite, albendazole sulfone, a process that is also mediated by CYP450; however, the precise isoforms responsible for this process remain unclear . Because of the involvement of CYP 3A isoenzymes in the formation of the active metabolite, it is not surprising that inhibitors of CYP 3A, such as ritonavir, as well as inducers, such as phenytoin, may influence plasma concentrations of albendazole sulfoxide …”