Chiral behaviour of the metabolite albendazole sulphoxide in sheep, goats and cattle

Delatour, P.; Garnier, François; Benoît, Etienne; Caude, I.

doi:10.1016/0034-5288(91)90095-6

Cited by 82 publications

(59 citation statements)

References 15 publications

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“…For example, the (ϩ) ABZSO enantiomer represents 91% of the total ABZSO plasma area under the concentration versus time curve (AUC) in cattle and 86% in sheep (Delatour et al, 1991). Such enantioselective kinetic disposition of ABZSO enantiomers was attributed to the relative contribution of the FMO-and P450-dependent oxygenases to ABZ sulfoxidation, which was confirmed in the current work.…”

Section: Virkel Et Alsupporting

confidence: 82%

“…The (ϩ) ABZSO enantiomer predominates in plasma (Delatour et al, 1991;Cristofol et al, 2001) and in tissues of parasite location such as lung and GI mucosa (Cristofol et al, 2001), as well as in a target parasite such as the liver fluke Fasciola hepatica . For example, the (ϩ) ABZSO enantiomer represents 91% of the total ABZSO plasma area under the concentration versus time curve (AUC) in cattle and 86% in sheep (Delatour et al, 1991).…”

Section: Virkel Et Almentioning

confidence: 99%

“…Such enantioselective kinetic disposition of ABZSO enantiomers was attributed to the relative contribution of the FMO-and P450-dependent oxygenases to ABZ sulfoxidation, which was confirmed in the current work. Moreover, it has been shown that (Ϫ) ABZSO, rather than its (ϩ) antipode, would be the main substrate for the P450-mediated formation of the inactive ABZSO 2 metabolite (Delatour et al, 1991;Benoit et al, 1992), whereas (ϩ) ABZSO was shown to be the main substrate for a bacteria-mediated sulforeduction to ABZ in the rumen (Virkel et al, 2002). Unfortunately, the relative pharmacological potency of each ABZSO enantiomer is still unknown, but altogether, these observations may indicate a minor contribution of the (Ϫ) ABZSO enantiomer (compared with its antipode) to the overall clinical efficacy of ABZ.…”

Section: Virkel Et Almentioning

confidence: 99%

“…Thus, two ABZSO and OFZ enantiomers have been identified (by chiral separation) in the plasma of sheep after administration of ABZ, FBZ (prochiral molecules) (Delatour et al, 1990), and OFZ (Sánchez et al, 2002). It has been shown that (ϩ) ABZSO is the main enantiomeric form recovered in plasma (Delatour et al, 1991) and in tissues of parasite location following ABZ treatment to sheep and ABZSO administration to cattle (Cristofol et al, 2001). Similarly, (ϩ) OFZ prevails in the systemic circulation after both FBZ (Delatour et al, 1990) and OFZ (Sánchez et al, 2002) administration to sheep.…”

mentioning

confidence: 99%

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Comparative Hepatic and Extrahepatic Enantioselective Sulfoxidation of Albendazole and Fenbendazole in Sheep and Cattle

Virkel¹,

Lifschitz²,

Sallovitz³

et al. 2004

Drug Metab Dispos

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ABSTRACT:The enantioselective sulfoxidation of the prochiral anthelmintic compounds albendazole (ABZ) and fenbendazole (FBZ) was investigated in liver, lung and small intestinal microsomes obtained from healthy sheep and cattle. The microsomal fractions were incubated with a 40 M concentration of either ABZ or FBZ. Inhibition of the flavin-containing monooxygenase (FMO) system was carried out by preincubation with 100 M methimazole (MTZ) either with or without heat pretreatment (2 min at 50°C). ABZ and FBZ were metabolized to the (؉) and (؊) enantiomers of their sulfoxide metabolites, named albendazole sulfoxide (ABZSO) and oxfendazole (OFZ), respectively. ABZ sulfoxidation rates were higher (p < 0.001) than those observed for FBZ. The FMO-mediated liver sulfoxidation of ABZ was enantioselective (100%) toward the (؉) ABZSO production in both species. Liver sulfoxidation of FBZ by FMO was also enantioselective toward (؉) OFZ (sheep ‫؍‬ 65%; cattle ‫؍‬ 79%). Cytochrome P450 was found to be mainly involved in the production of (؊) ABZSO in the liver. MTZ did not affect the sulfoxidation of ABZ by lung microsomes, which may indicate that FMO is not involved in the production of ABZSO in this tissue. A significant (p < 0.05) inhibition of (؊) ABZSO production by liver microsomes was observed after ABZ incubation in the presence of erythromycin (cattle ‫؍‬ 21%) and ketoconazole (sheep ‫؍‬ 36%). Both CYP3A substrates induced a reduction in the production of (؊) ABZSO (sheep ‫؍‬ 67-78%, cattle ‫؍‬ 50-78%) by lung microsomes. Overall, the results reported here contribute to the identification of the metabolic pathways involved in the biotransformation of benzimidazole anthelmintics extensively used for parasite control in ruminants.Livestock animals are exposed to a variety of xenobiotic agents (i.e., veterinary drugs, feed-additives, pesticides, pollutants, etc.) during their production cycles. These compounds are likely to be metabolized by different enzymatic systems from both hepatic and extrahepatic tissues. The metabolic activity of the flavin-containing monooxygenase (FMO) and cytochrome P450 (P450) systems plays a major role in determining the persistence of therapeutically used drugs in target species, which may additionally impose a risk to the consumer as a consequence of the permanence of drug residue levels in edible tissues. Metabolic interactions with either the FMO or P450 enzymatic systems may drastically affect the disposition kinetics of different drugs used in animal production, which will have a relevant impact on the pattern of drug/metabolite residues in edible tissues, a major concern for public health and consumer safety.Benzimidazole (BZD 1 ) and pro-BZD anthelmintics are extensively metabolized in domestic animals and humans. Their metabolic pattern and the resultant pharmacokinetic behavior are relevant in the attainment of high and sustained concentrations of pharmacologically active drug/metabolites at the target parasite . Albendazole (ABZ; methyl-[(5-propylthio)-1H-benzimidazol-2-yl] carba...

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Section: Virkel Et Alsupporting

confidence: 82%

Section: Virkel Et Almentioning

confidence: 99%

Section: Virkel Et Almentioning

confidence: 99%

mentioning

confidence: 99%

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Comparative Hepatic and Extrahepatic Enantioselective Sulfoxidation of Albendazole and Fenbendazole in Sheep and Cattle

Virkel¹,

Lifschitz²,

Sallovitz³

et al. 2004

Drug Metab Dispos

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“…Multiple enzymes participate in ABZSO enantiomer formation: CYP3A generates mainly ( )-ABZSO while the FMO produce (+)-ABZSO [10]. In domestic sheep and mouflon, (+)-ABZSO formation predominates [42,43]. In our experiments, the (+)-ABZSO/(-)-ABZSO ratio shifted from 1.5 in the non-infected animals to 1.7 in the D-infected animals.…”

Section: Discussionmentioning

confidence: 58%

Dicrocoeliosis of Old Mouflon Ewes - Effect on Biotransformation Enzymes and Metabolism of Anthelmintics In Vitro

Křížová¹,

Lamka²,

Szotáková³

et al. 2008

TOVSJ

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Parasitic infections can modify the host's ability to metabolize drugs by altering the biotransformation enzymes. Mouflon (Ovis musimon), the wild sheep, is very sensitive to parasitic diseases. In the present study, in vitro activities of thirteen hepatic biotransformation enzymes and the in vitro metabolism of albendazole and flubendazole were compared in old mouflon ewes, either non-infected or infected with lancet flukes (Dicrocoelium dendriticum). The most pronounced decline in 6 testosteron hydroxylase, glutathione-S-transferase and UDP-glucuronosyl transferase activities was observed in Dicrocoelium-infected animals. In addition, dicrocoeliosis caused a decrease in both albendazole and flubendazole phase I hepatic metabolism. However, the changes were very slight therefore any undesirable alterations in albendazole and flubendazole pharmacokinetics are not expected. Decreased activities of 6 testosterone hydroxylase, glutathione-S-transferase and UDP-glucuronosyl transferase can impair drug elimination from the infected animals. This should be taken into consideration in pharmacotherapy or pharmacoprophylaxis of mouflons and sheep.

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Enantioselective kinetic disposition of albendazole sulfoxide in patients with neurocysticercosis

et al. 1999

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Chiral behaviour of the metabolite albendazole sulphoxide in sheep, goats and cattle

Cited by 82 publications

References 15 publications

Comparative Hepatic and Extrahepatic Enantioselective Sulfoxidation of Albendazole and Fenbendazole in Sheep and Cattle

Comparative Hepatic and Extrahepatic Enantioselective Sulfoxidation of Albendazole and Fenbendazole in Sheep and Cattle

Dicrocoeliosis of Old Mouflon Ewes - Effect on Biotransformation Enzymes and Metabolism of Anthelmintics In Vitro

Enantioselective kinetic disposition of albendazole sulfoxide in patients with neurocysticercosis

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