In Vitro Analysis of Albendazole Sulfoxide Enantiomers Shows that (+)-( R )-Albendazole Sulfoxide Is the Active Enantiomer against Taenia solium

Abstract

Albendazole is an anthelmintic drug widely used in the treatment of neurocysticercosis (NCC), an infection of the brain with Taenia N eurocysticercosis (NCC) is a major cause of adult-onset seizures and epilepsy in many areas of the developing world. It is an infection with the larval cyst form of the cestode tapeworm Taenia solium acquired through the accidental ingestion of ova shed in the feces of human tapeworm carriers. The released oncospheres find their way to the bloodstream and are carried throughout the body but develop mostly in the muscles, subcutaneous tissues, and brain. Almost all the symptoms are due to brain involvement (1).Two drugs, the benzimidazole albendazole (ABZ) and the pyrazinoisoquinoline praziquantel (PZQ), are commonly used to treat neurocysticercosis, usually with accompanying immunosuppressive/anti-inflammatory medication (2-4). Albendazole is frequently preferred to praziquantel because it is more widely available, has a lower cost, and normally requires shorter courses of treatment (and hence represents lower hospitalization-associated expenses) for higher efficacy (2, 5-7).In susceptible parasites, the main effect of ABZ is the inhibition of tubulin polymerization into microtubules, but the drug also causes biochemical changes such as inhibition of mitochondrial fumarate reductase, reduced glucose transport, and uncoupling of oxidative phosphorylation, impairing ATP generation (8, 9). Although ABZ has been used since the 1970s (10, 11), it is not completely effective in killing cysts; 12% and 45% of total cysts remain after the usual dosing regimens used with albendazole and praziquantel, respectively (12). Cure rates are unacceptably low for both drugs at about 40% to 50%, so retreatments are often required.After oral administration, the nonchiral ABZ is oxidized in the liver to its active metabolite, albendazole sulfoxide (ABZSO), with one chiral center in the sulfoxide group. The two possible enan- (13), show different pharmacokinetics and affinities for cytosolic proteins from different parasites (28). Kinetic parameters of (ϩ)-(R)-and (Ϫ)-(S)-ABZSO enantiomers in NCC patients treated with ABZ differ in renal excretion (14), accumulation in plasma (15), and, most importantly, distribution in the cerebrospinal fluid (12). Even though the levels of effectiveness of the two enantiomers against a number of other helminths differ, the effect of the isolated enantiomers against T. solium metacestodes (cysts) has not been reported. tiomers, (ϩ)-(R)-and (Ϫ)-(S)-ABZSOA sensitive in vitro system to quantify drug effects on cysts of T. solium has been recently reported (16). In this system, drug sensitivity to both ABZSO and PZQ correlates with the degree of inhibition of alkaline phosphatase (AP) release from cysts, obtained from naturally infected pigs and cultured in vitro (16). Using this system, we compared the anthelmintic effect of the (ϩ)-(R)-and (Ϫ)-(S)-ABZSO enantiomers to effects of the ABZSO racemic mixture and of PZQ. Here we show that the antiparasitic effect of the drug ...

Quorum sensing N-Acyl homoserine lactones are a new class of anti-schistosomal

“…Furthermore, Paredes et al demonstrated that ( R )-albendazole sulfoxide had greater anthelmintic activity against T . solium when compared to ( S )-albendazole [ 45 ]. Our data, along with these and other parasitic studies [ 46 ], provides clear evidence that compound chirality represents an important consideration for drug discovery progression and putative target identification.…”

Exploiting the Power of Stereochemistry in Drugs: An Overview of Racemic and Enantiopure Drugs

“…Albendazole is an anthelmintic drug widely used in the treatment of neurocysticercosis, an infection of the brain with Taenia solium cysts. Use of (+)-(R)-Albendazole sulfoxide ( Figure 12) enantiomer alone may lead to increased efficacy and/or less toxicity compared to albendazole [59]. Mephedrone (Figure 13) most probably as a racemic mixture of the R and S enantiomers is a synthetic psychoactive substance.…”

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

“…After absorption, albendazole is subject to rapid and extensive first‐pass metabolism into the chiral metabolite, albendazole sulfoxide, which is the entity responsible for its cysticidal activity . The (+)‐ enantiomer of albendazole sulfoxide has the greatest pharmacologic activity against T. solium . Albendazole is subject to high intrinsic clearance which may be a result of poor absorption, extensive first pass metabolism, or a combination of these factors.…”

“…10 The (þ)-enantiomer of albendazole sulfoxide has the greatest pharmacologic activity against T. solium. 11 Albendazole is subject to high intrinsic clearance 12 which may be a result of poor absorption, extensive first pass metabolism, or a combination of these factors. Albendazole sulfoxide also exhibits plasma protein binding (62-72%).…”