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R K Prichard

Publications and source records attributed to R K Prichard.

At least 19 recordsLinked to original sources
PubMed1997

Reversal of P-glycoprotein-associated multidrug resistance by ivermectin.

P-Glycoprotein (P-gp) causes a multidrug resistance (MDR) phenotype in tumour cells. In some cancers, the expression of P-gp has been correlated with low clinical response to chemotherapy and survival of patients. Previous studies have shown that certain lipophilic drugs bind to P-gp and reverse the MDR phenotype of tumour cells. In this study, we extend that list of compounds and present evidence for the capacity of a potent and clinically safe anthelmintic, ivermectin (IVM), as an MDR-reversing drug. Using a highly drug-resistant human cell line, we compared IVM with other MDR-reversing agents and showed that IVM is 4- and 9-fold more potent than cyclosporin A and verapamil, respectively. The capacity of IVM to inhibit iodoaryl-azidoprazosin photolabeling of P-gp is consistent with direct binding to P-gp. Studies showed that [3H]IVM binding to membranes from resistant cells is specific and saturable with KD and Bmax values of 10.6 nM and 19.8 pmol/mg, respectively. However, while cyclosporin A or vinblastine inhibited [3H]IVM binding to membranes from drug-resistant but not drug-sensitive cells, neither verapamil nor colchicine had any effect. Furthermore, both IVM and cyclosporin A and, to a lesser extent, verapamil also inhibited [3H]vinblastine binding to membranes from drug-resistant cells. Drug transport studies showed that [3H]IVM is a substrate for the P-gp drug efflux pump. However, it was transported less efficiently by P-gp than [3H]vinblastine. Moreover, only cyclosporin A was effective in potentiating the accumulation of [3H]IVM in drug-resistant cells. Taken together, the high efficiency of MDR reversal by IVM combined with its low toxicity are consistent with the properties of an ideal MDR-reversing agent.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Effects of three nematode anthelmintic treatment regimes on flock performance of sheep and goats under extensive management in semi-arid Kenya.

A study was undertaken in a semi-arid area of Kenya between August 1991 and June 1993 to evaluate the effects of anthelmintic treatment using ivermectin before or during the rains, on performance of mixed sheep and goat flocks, in comparison with an untreated flock. Performance parameters measured included age and weight of dams at first parturition, parturition intervals, body weights of dams and offspring, and birth weights, growth rates, and mortality rates of offspring. Among these parameters, birth weights and growth rates of offspring were found to be significantly improved by the treatment administered before the rains compared with the other two treatments. Mortality was lower in lambs and kids with high birth weights. Treatment, either before or during the rains, significantly reduced the faecal egg output and improved body weight, packed cell volume and flock fertility. Liveweight was confirmed to be a better measure of sexual maturity than age. It was further shown that lambs and kids, born of dams at their first lambing or kidding, experienced higher mortality rates than lambs and kids born of dams in their second and subsequent parturitions. Overall, treatment with ivermectin before the onset of rains was equal to or better, in terms of the performance parameters measured, than treatment during the rains, whilst treatment compared with no treatment increased performance in almost all of the parameters measured.

Albendazole↗
PubMed1996

p-Azidosalicyl-5-amino-6-phenoxybenzimidazole photolabels the N-terminal 63-103 amino acids of Haemonchus contortus beta-tubulin 1.

Benzimidazoles (BZ) are broad spectrum anthelmintics thought to exert their effects by interacting with and disrupting the functions of microtubules. However, direct biochemical evidence for binding between BZ and tubulin has not been shown nor is it known what sequences in tubulin interact with BZ. In this study, a photoactive analogue of 2-acetamido-5-(3-aminophenoxy)benzimidaz ole that has biological activity similar to other benzimidazoles was synthesized and used to photoaffinity label cell lysates from the parasitic nematode of sheep Haemonchus contortus. The photoactive analogue, 2-acetamido-5-[3-(4-azido-3-125I-salicyl amido)phenoxy]benzimida zol e or 125I-ASA-BZ, was shown to photolabel a 54-kDa protein that was specifically immunoprecipitated with anti-tubulin monoclonal antibodies. Tubulin photoaffinity labeling by 125I-ASA-BZ was also inhibited with molar excess of various BZ analogues and colchicine. Interestingly, 125I-ASA-BZ photoaffinity-labeled the beta- and not the alpha-subunits of tubulin. Proteolytic digestion of 125I-ASA-BZ-labeled tubulin with Staphylococcus aureus V8 proteinase revealed one major peptide with an apparent molecular mass of 3.5 kDa. Exhaustive digestion of 125I-ASA-BZ-labeled beta-tubulin with trypsin resulted in two fractions containing radioactive peptides. Protein sequencing of the high performance liquid chromatography-purified tryptic ASA-BZ-photolabeled peptides identified the N-terminal 63-77 and 78-103 sequences as the BZ binding domain.

Affinity Labels↗
PubMed1995

Influence on the antithyroid compound methimazole on the plasma disposition of fenbendazole and oxfendazole in sheep.

The influence of methimazole on the plasma disposition kinetics of fenbendazole, oxfendazole and their metabolites, was investigated in adult sheep. The two anthelmintics were administered by oral drench at 5 mg kg-1 either alone (control treatments) or together with methimazole given orally at 3 mg kg-1. Blood samples were taken serially for 144 hours. Fenbendazole parent drug and its sulphoxide and sulphone metabolites were the three analytes observed by high performance liquid chromatography (HPLC) after the administration of both anthelmintics. The disposition of each analyte followed a similar pattern after the administration of the two anthelmintics alone. Oxfendazole was the main component recovered in plasma between four and 120 to 144 hours after the administration of both anthelmintics either with or without methimazole. A modified pattern of disposition, with significantly higher Cmax and AUC values for fenbendazole parent drug, and a delayed appearance in plasma with retarded Tmax values for the sulphoxide and sulphone metabolites, were the main pharmacokinetic changes observed when the drugs were administered with methimazole.

Animals↗
PubMed1995

Comparative plasma disposition kinetics of albendazole, fenbendazole, oxfendazole and their metabolites in adult sheep.

The comparative plasma disposition kinetics of albendazole (ABZ), fenbendazole (FBZ) and oxfendazole (OFZ) following their oral administration (5 mg/kg) to adult sheep was characterized. Jugular blood samples were taken serially over a 144 h period and plasma was analysed by high performance liquid chromatography (HPLC) for ABZ, ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO2) (ABZ treatment), and for FBZ, OFZ and FBZ sulphone (FBZSO2) (FBZ and OFZ treatments). While the ABZ parent drug was not detected at any time post-treatment, ABZSO and ABZSO2 were the analytes recovered in plasma after oral administration of ABZ to sheep. The active ABZSO metabolite was the main analyte recovered in plasma (between 0.25 and 60 h post-treatment), accounting for 71% of the total AUC. FBZ, OFZ and FBZSO2 were the analytes detected in plasma following the oral administration of both FBZ and OFZ to sheep. Low concentrations of FBZ were found in plasma between 4 (FBZ treatment) or 8 h (OFZ treatment) and 72 h post-treatment. The plasma profile of each analyte followed a similar pattern after both treatments; OFZ being the main component detected in plasma. The plasma disposition of ABZ metabolites was markedly different to that of FBZ derivatives. ABZSO exhibited faster absorption and a higher Cmax than OFZ (both treatments). Furthermore, while ABZSO declined relatively rapidly in plasma reaching non-detectable concentrations at 60 h post-ABZ administration, OFZ was found in plasma for up to 120 (FBZ treatment) and 144 h (OFZ treatment).(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1994

Benzimidazoles, potent anti-mitotic drugs: substrates for the P-glycoprotein transporter in multidrug-resistant cells.

P-glycoprotein is though to mediate the energy-dependent efflux of many structurally and functionally unrelated lipophilic compounds. Presently, the molecular mechanism underlying the binding and efflux of drugs by P-glycoprotein is not well understood. However, it has been suggested that two planar benzene ring structures and a cationic charge are commonly found in many drugs that interact with P-glycoprotein. The benzimidazoles (BZs) are potent anti-tumour, anti-fungal and anti-parasitic agents, whose mode of action is thought to result from their inhibition of microtubule functions. Although other classes of microtubule inhibitors, such as colchicine and vinblastine, have been studied extensively with respect to their interaction and efflux by P-glycoprotein, the BZ group of drugs has not been characterized. In this study, we have characterized the interaction of BZ with multidrug-resistant cells and found that resistant cells accumulated substantially less BZ compared with drug-sensitive cells. Furthermore, BZ was more toxic to sensitive than to drug-resistant cells, suggesting that BZ is likely to be a substrate for the P-glycoprotein drug efflux pump. In addition, we used a photoactive analogue of BZ ([125I]ASA-BZ) to demonstrate a direct binding between BZ and P-glycoprotein. Results showing that a molar excess of vinblastine, unmodified BZ, verapamil and rhodamine 123, but not colchicine, inhibited the photoaffinity labelling of P-glycoprotein by [125I]ASA-BZ confirmed the binding specificity of BZ to P-glycoprotein. Protease digestion of [125I]ASA-BZ photoaffinity labelled P-glycoprotein yielded two peptides that were similar to those obtained with other P-glycoprotein-associated drugs, e.g. azidopine and iodoaryl azidoprazosin. Taken together, these results demonstrate a direct and specific interaction between P-glycoprotein and BZ in a manner that is probably similar to other previously characterized P-glycoprotein-associated drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Haemonchus contortus: the role of two beta-tubulin gene subfamilies in the resistance to benzimidazole anthelmintics.

The role of beta-tubulin genes in benzimidazole (BZ) resistance was investigated using one susceptible (S) and two resistant (Rt and Rc) strains of Haemonchus contortus. The Rt strain was isolated from the field on the basis of thiabendazole resistance. The Rc strain was derived from the S strain by treatment with cambendazole. cDNAs, derived from the S strain, encoding two isoforms of beta-tubulin (beta 12-16 and beta 8-9), alpha-tubulin and phosphofructokinase (Pfk) were used as probes for Southern hybridization analysis of genomic DNA digested by restriction enzymes. Genomic DNA was isolated from a pool of worms or single worms. The restriction-enzyme fragment length polymorphism (RFLP) differences among these strains depended on the enzyme and the probe used. When digested with Stu I or Hpa I, and probed under stringent conditions with beta 8-9 or beta 12-16, fewer fragments were seen in the Rt and Rc strains than in the S strain. Different hybridizing fragments were found in different individuals. The frequency of individuals bearing certain fragments hybridizing to beta 12-16 or beta 8-9 in the susceptible population was reduced significantly in the resistant populations. Some differences in RFLP between these strains were observed when probed with alpha-tubulin or Pfk, but the changes were not consistent with fragments being lost from the resistant strains as observed for beta-tubulin probes. These changes in RFLP pattern correlate with changes in the binding profiles of BZs and isoelectric isoform patterns reported previously for these strains. The data confirm that reduced heterogeneity within the population is associated with BZ resistance. Our results show that both the beta 8-9 and the beta 12-16 subfamilies of beta-tubulin are affected to a similar extent by this reduction in heterogeneity in a resistant population.

Animals↗
PubMed1994

Reduction in tissue egg load and maintenance of resistance to challenge in mice infected with Schistosoma mansoni, following combined treatment with praziquantel and an antifibrotic agent.

Antifibrotic therapy with beta-aminoproprionitrile (BAPN), when combined with praziquantel (PZQ) treatment of mice infected with Schistosoma mansoni, led to a marked change in the temporal pattern of parasite egg excretion. The rate of egg excretion was higher and terminated sooner and the tissue egg load was smaller in mice treated with BAPN and PZQ than in mice treated with PZQ alone. Some of the mice that received the combined treatment were challenged 2 or 5 weeks after PZQ treatment; they retained a high level of resistance to challenge, similar to that observed in untreated, infected mice. In contrast, mice given only PZQ were as susceptible to challenge as the uninfected control mice. The activity of peritoneal macrophages, as measured by their production of hydrogen peroxide, nitric oxide and tumour necrosis factor alpha in vitro, was only elevated in cells obtained from untreated, infected mice. These results demonstrate that modulation of granuloma formation by combined antifibrotic/PZQ therapy significantly changes the dynamics of egg granuloma formation and attenuates the host's resistance to challenge infection.

Aminopropionitrile↗
PubMed1994

Genetic variability of the beta-tubulin genes in benzimidazole-susceptible and -resistant strains of Haemonchus contortus.

Benzimidazole anthelmintics are the most common chemotherapeutic agents used to remove intestinal helminths from farm animals. The development of drug resistance within helminth populations is wide-spread and can render these drugs essentially useless. The mechanism of benzimidazole resistance appears to be common to many species ranging from fungi to nematodes and involves alterations in the genes encoding beta-tubulin. During the selection process resulting in resistance, there must be quantitative changes in the population gene pool. Knowledge of these changes would indicate the mechanisms underlying the spread of resistance in the population, which in turn could be used to design more effective drug administration strategies. To this end we have identified allelic variation at two beta-tubulin genes in Haemonchus contortus using restriction map analysis of individual adults. Extremely high levels of variation were identified at both loci within a susceptible strain. In two independently derived benzimidazole resistant strains, allele frequencies at both loci were significantly different from the susceptible strain but not from each other. The same alleles at both loci, in both resistant strains, were favored by selection with benzimidazoles, suggesting that both loci are involved in determining benzimidazole resistance. These data confirm that changes in allele frequency, rather than novel genetic rearrangements induced by exposure to the drug, explain the changes associated with benzimidazole resistance. These results also show that any DNA based test for the development of benzimidazole resistance must take into account the frequency of alleles present in the population and not simply test for the presence or absence of specific allelic types.

Alleles↗
PubMed1994

Characterization of rhodamine 123 binding to P-glycoprotein in human multidrug-resistant cells.

The overexpression of P-glycoprotein is currently believed to be responsible for the enhanced efflux or decreased influx of cytotoxic drugs across the cell membrane in drug-resistant cells. P-glycoprotein has been proposed to mediate the efflux of a large number of structurally and functionally unrelated drugs. Although it has been suggested that P-glycoprotein binds directly to many lipophilic cations, it remains unclear whether one or more sites in P-glycoprotein mediate its broad substrate specificity. In this report, a photoactive derivative of rhodamine 123 (Rh123) [125I-azidosalicylic acid (ASA)-Rh123] was synthesized and used in a photoaffinity labeling assay to demonstrate, for the first time, direct and specific binding to P-glycoprotein. The photoaffinity labeling of P-glycoprotein by ASA-Rh123 was specifically inhibited in the presence of vinblastine and verapamil but not in the presence of colchicine. Surprisingly, ASA-Rh123 photoaffinity labeled a 6-kDa V8 peptide in P-glycoprotein that was previously shown to be photoaffinity labeled by another multidrug resistance-associated drug, [125I]iodoarylazidoprazosin. Photoaffinity labeling of mitochondria from drug-sensitive or -resistant cells with 125I-ASA-Rh123 did not reveal significant differences in the mitochondrial proteins from sensitive or resistant cells. Interestingly, however, 125I-ASA-Rh123 did photolabel a 66-kDa protein in mitochondria that was not detected in plasma membrane preparations with this assay. Taken together, our results demonstrate for the first time that Rh123 binds specifically to P-glycoprotein and that its binding site may be shared by other multidrug resistance-associated drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Interaction of mebendazole with tubulin from body wall muscle, intestine, and reproductive system of Ascaris suum.

The binding of tritiated mebendazole, a benzimidazole anthelmintic, to tubulin derived from intestine, body wall muscle, and reproductive system of adult Ascaris suum was examined and compared. Mebendazole binding was resolved into specific and nonspecific binding and the binding affinity (Ka) and maximum binding at infinite ligand concentration (Bmax) determined. Electron microscopy was performed to assess the tubulin in various tissues of A. suum quantitatively by observing the presence of microtubules. Total binding was highest in intestine followed by body wall muscle. It was least in the reproductive system. The intestine demonstrated greater specific binding per milligram of protein than the body wall muscle. However, in the reproductive system extract, high affinity binding was not detected. After correction for nonspecific binding of ligand, the results indicated that the Bmax of mebendazole for the tubulin of A. suum intestine was about 3-fold higher than for that of body wall muscle. The Ka of mebendazole for intestinal tubulin was similar to that for body wall muscle. Electron microscopy of A. suum tissues demonstrated that the tubulin content decreased from the intestine through the body wall muscle to the reproductive system. Differences in tubulin content from different tissues may determine the selective sensitivity of these tissues to benzimidazole attack.

Animals↗
PubMed1993

Expression of cloned beta-tubulin genes of Haemonchus contortus in Escherichia coli: interaction of recombinant beta-tubulin with native tubulin and mebendazole.

Two distinct beta-tubulin cDNA isotypes (beta 8-9 and beta 12-16) from Haemonchus contortus were expressed for the first time in Escherichia coli and characterised by their specific mebendazole (MBZ) binding and polymerization properties. Beta-tubulin was expressed without translational fusion to an E. coli sequence under the regulation of the tryptophan promoter in the pTrp2 vector. Beta-tubulin was produced in large amounts in insoluble 'inclusion bodies'. The inclusion bodies were purified and solubilised and the beta-tubulin renatured by treatment with urea followed by dilution with alkaline buffer and a shift to physiological pH. The yield was more than 10 mg of beta-tubulin per litre of cell culture. The recombinant tubulin produced was recognized in Western blot by specific anti-beta-tubulin antibodies. Tritiated MBZ binding to the recombinant H. contortus beta-tubulin was measured in the presence or absence of whole, tubulin-free or tubulin-rich extracts of H. contortus. Some [3H]MBZ high-affinity binding (HB) to 'pure' (no other eukaryotic protein present) beta 8-9 or beta 12-16 was observed. Enhanced high-affinity binding was observed when recombinant beta 8-9 or beta 12-16 were mixed and pre-incubated with whole supernatants or tubulin-enriched extracts from H. contortus. The enhancement was more than additive. Beta 12-16 bound more MBZ and caused a greater enhancement than beta 8-9. Mixing recombinant beta 8-9 or beta 12-16 with whole supernatants or tubulin-enriched fractions from H. contortus promoter polymerization at 37 degrees C. Use of 35S-labelled protein showed that the polymer contained recombinant tubulin. Western blot using specific anti-alpha-tubulin monoclonal antibodies showed that the polymer contained alpha-tubulin. Similarly the recombinant nematode beta-tubulin co-polymerized with tubulin from chicken brain. Our data suggest that the recombinant beta-tubulin can interact and copolymerize with parasite or chicken tubulin. Furthermore the interaction of recombinant nematode beta-tubulin with native tubulin and/or microtubule associated proteins (MAPs) resulted in the formation of high-affinity MBZ-binding sites. However, interaction of recombinant beta-tubulin with microtubule proteins from chicken brain did not result in the formation of high-affinity MBZ-binding sites.

Animals↗
PubMed1993

Anthelmintics.

Anthelmintics remain the principal means for the prevention and control of subclinical and clinical ostertagiasis. The selection of an appropriate anthelmintic depends on whether one is controlling or preventing Type I ostertagiasis (caused by the establishment of adult worms derived from recently acquired infective larvae), preventing Type II (treating pre-Type II or inhibited larvae) or controlling Type II ostertagiasis (caused by the development of inhibited larvae to adults), or using the anthelmintic as part of an epidemiologically based plan to reduce pasture contamination with infective Ostertagia ostertagi larvae. In the latter case, the choice of an anthelmintic may depend on whether the targets for treatment are only adult worms and developing larvae or whether the targets include hypobiotic larvae. Thus for Ostertagia control, anthelmintics must be divided into those that normally control all stages, such as the avermectin group (ivermectin, abamectin and moxidectin) and some of the benzimidazoles (albendazole, oxfendazole and fenbendazole at appropriate dose rates), and those that only control adult worms and developing larvae (levamisole, morantel, coumaphos, phenothiazine and thiabendazole).

Animals↗
PubMed1993

Relationship between pharmacological properties and clinical efficacy of ruminant anthelmintics.

The purpose of this review article is to establish a relationship between pharmacological properties and clinical efficacy of the most widely used broad-spectrum veterinary anthelmintics. The impact of drug pharmacokinetics/pharmacodynamics on anthelmintic efficacy and resistance is discussed. We review the clinical pharmacokinetics of the currently available anthelmintics used in livestock-imidazothiazoles, tetrahydropyrimidines, benzimidazoles/pro-benzimidazoles, salicylanilides (closantel) and avermectin-type compounds. Understanding the pharmacokinetic and metabolic behaviour of broad-spectrum anthelmintics in the host, and factors modulating that behaviour, is highly important for maximizing anthelmintic utility and efficacy.

Animals↗
PubMed1993

Biliary secretion and enterohepatic recycling of fenbendazole metabolites in sheep.

Fenbendazole (FBZ) was administered intraruminally at 5.0 mg/kg, containing a trace of [14C]-FBZ, to sheep fitted with a permanent bile duct cannula and the behaviour of FBZ and its metabolites examined in bile and plasma. Of the administered radiolabelled dose, 47% was secreted in bile of which 34% was accounted for as conjugated and 4% as unconjugated (free) metabolites. Hydroxylated oxfendazole (OH.OFZ) was the major biliary metabolite contributing 66%, and hydroxy-FBZ (OH.FBZ) 27%, of the total metabolites characterized. Small amounts of OFZ and hydroxy FBZ sulphone (OH.FBZ.SO2) were also present in bile. The rapid appearance of OH.OFZ in bile, even before maximum concentrations of OFZ occurred in plasma, indicated that sulphoxidation and hydroxylation was the major route of FBZ metabolism. Following intraduodenal infusion of free biliary metabolites, FBZ and its metabolites rapidly appeared in bile indicating absorption from the small intestine. When conjugated metabolites were infused they continued to appear in bile for a further 15-20 h after cessation of infusion indicating that absorption of hydroxylated metabolites occurred largely after bacterial deconjugation in the large intestine. Approximately 40% of biliary metabolites were estimated to undergo enterohepatic reabsorption but they contributed minimally to the metabolite content in plasma. It is suggested that during the process of recycling-biliary metabolites make substantial contact with parasites in the mucosa of the small and large intestine thereby contributing to the anti-helminthic activity of FBZ.

Absorption↗
PubMed1993

Gastrointestinal distribution of albendazole metabolites following netobimin administration to cattle: relationship with plasma disposition kinetics.

The gastrointestinal (GI) distribution and plasma disposition kinetics of albendazole (ABZ) metabolites after oral administration of netobimin (NTB) to cattle were studied. Eight Holstein steers (150-180 kg) were surgically fitted with permanent cannulae in the rumen, abomasum and ileum. After post-surgical recovery, the animals were treated orally with a suspension of netobimin zwitterion (400 mg/ml) at 20 mg/kg. Jugular blood and ruminal, abomasal and ileal fluid samples were taken serially over a 96 h period and analysed by HPLC for NTB and its metabolites, including ABZ, ABZ sulphoxide (ABZSO), ABZ sulphone (ABZSO2) and amino-albendazole sulphone (NH2ABZSO2). NTB parent drug was only found in the GI tract and for only 12-18 h post-treatment. ABZSO and ABZSO2 were the main metabolites found in plasma, being present for 30-36 h. These metabolites were exchanged between plasma and different GI fluids and were greatly concentrated in the abomasum. This phenomenon may account for the presence of ABZ, ABZSO and ABZSO2 in the GI tract for 72 h post-treatment despite the fact that ABZ was not detected in plasma and ABZSO and ABZSO2 were detected for only 30-36 h in plasma. The presence of ABZ and ABZSO in the abomasum and intestine for this extended period of time is probably relevant for anthelmintic efficacy against GI parasites. The NH2 ABZSO2 metabolite was detected in plasma, abomasum and ileum and its disposition kinetics were characterized for the first time.

Abomasum↗
PubMed1993

Comparative sulphoxidation of albendazole by sheep and cattle liver microsomes and the inhibitory effect of methimazole.

1. The comparative rates of oxidation of the benzimidazole anthelmintic, albendazole (ABZ), by sheep and cattle liver microsomes, and inhibition by the antithyroid compound methimazole (MTZ) were investigated. 2. ABZ was oxidized to its sulphoxide metabolite (ABZSO) in an NADPH concentration-dependent reaction. Heat inactivation of the microsomal flavin-containing mono-oxygenase system significantly decreased the NADPH consumption of microsomes in the presence of ABZ, MTZ and thiourea. 3. Oxidation of ABZ, MTZ and thiourea by sheep liver microsomes consumed significantly more NADPH than oxidation by cattle microsomes. 4. Neither the pro-ABZ drug, netobimin, nor the ABZ sulphone metabolite (ABZSO2) was modified by incubation with either sheep or cattle liver microsomes. 5. ABZSO was oxidized into ABZSO2 at a very slow rate and only when a high microsomal protein concentration was used. 6. MTZ was a potent inhibitor of ABZ sulphoxidation and the inhibition was significantly lower in cattle than in sheep microsomes.

Albendazole↗