C282Y hemochromatosis gene mutation and iron parameters in dialysis patients.

BACKGROUND: Hereditary hemochromatosis is an autosomal recessive condition causing excessive intestinal iron absorption related to C282Y hemochromatosis mutation gene. Dialysis patients receive intravenous iron supplements as treatment for anemia. The gene mutation frequency and its influence on iron deposits and intravenous iron response are unknown in these patients. STUDY DESIGN: Prospective observational. SETTING AND PARTICIPANTS: 290 dialysis patients in Gran Canaria, Spain. OUTCOMES AND MEASUREMENTS: The C282Y hemochromatosis mutation gene was studied. Other active players in iron metabolism have not been included in this study. Red cell parameters, serum iron, transferrin and ferritin concentrations were measured every 2 months for 2 years. RESULTS: No differences in allelic and genotypic frequencies between dialysis patients and the general population were detected. Baseline clinical or analytical parameters were similar in C282Y +/- and C282Y -/- patients. Among those who did not need intravenous iron treatment, C282Y+/- patients maintained constant serum ferritin (302.1 ± 216.7 vs. 319.5 ± 300.5 µg/l after 4 months), whereas C282Y-/- patients showed decreased levels during the same period (306.7 ± 212.2 vs. 221.6 ± 167.8 µg/l, p < 0.001). After 4 months of parenteral iron, serum ferritin increased more intensely in C282Y +/- patients than in C282Y -/- patients (934.2 ± 195.8 vs. 658.7 ± 259.9 µg/l, p < 0.001). A multivariance analysis identified the C282Y allele as the most important factor that explains this difference. CONCLUSIONS: Heterozygosity for the C282Y allele of the hemochromatosis mutation gene could be associated with differences in iron parameters in dialysis patients.

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)

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.

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.

Morantel tartrate release from a long-acting intraruminal device in cattle: pharmacokinetics and gastrointestinal distribution.

The pharmacokinetics and gastrointestinal distribution of morantel tartrate release from a sustained release trilaminate bolus in cattle were investigated over a 98-day period post-treatment. Six Holstein calves (125-150 kg) had permanent indwelling fistulae surgically inserted into the rumen, abomasum and terminal ileum. Samples of jugular blood, feces and ruminal, abomasal and ileal fluids were taken on days -3, 1, 4, 7, 10, 14 and weekly up to 98 days post-bolus administration. Morantel tartrate concentrations were measured by HPLC after extraction and clean-up. Morantel was not detected in plasma at any time after bolus administration. High concentrations of morantel tartrate were found in ruminal, abomasal and ileal fluids and feces over 98 days post-treatment. The morantel peak concentration (Cmax) was achieved at Day 1 post-administration in each of these compartments. The steady-state morantel concentration (Css) was achieved at approximately 10 days post-treatment and maintained for 91-98 days post-treatment in these gastrointestinal compartments. The morantel Cmax, Css, area under the zero (AUC) and first moment (AUMC) of the concentration-time curve were significantly higher (P less than 0.01) in feces than in other compartments. The in vivo drug release profile of this device has been determined. Steady-state concentrations for from 91 to 98 days have been confirmed.

Metabolism of albendazole and albendazole sulphoxide by ruminal and intestinal fluids of sheep and cattle.

1. The metabolism of albendazole (ABZ), albendazole sulphoxide (ABZSO) and albendazole sulphone (ABZSO2) by ruminal, abomasal and ileal fluids of sheep and cattle was investigated under anaerobic conditions in vitro. 2. None of the compounds was metabolically changed by incubation with abomasal fluids of sheep and cattle. 3. ABZ and ABZSO were extensively metabolized by sheep and cattle ruminal and ileal fluids. ABZSO2 was unaffected by incubation with these gastrointestinal fluids. 4. The rate of ABZ oxidation into ABZSO was greater for cattle ruminal and ileal fluids than for sheep fluids. 5. ABZSO was reduced back to ABZ by ruminal and ileal fluids of both species. This reducing activity was significantly higher for both ruminal and ileal fluids of sheep compared with those of cattle.

Bioconversion of netobimin pro-drug by gastrointestinal fluids of ruminants.

The biotransformation of netobimin (NTB) pro-drug by ruminal, abomasal and intestinal fluids of sheep and cattle was investigated under anaerobic conditions in vitro. No metabolic conversion of NTB was observed upon incubation with abomasal fluid or boiled samples of different gastrointestinal fluids. NTB pro-drug was reduced and cyclised into albendazole (ABZ) and this further oxidized into ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO2) by both sheep and cattle ruminal and ileal fluids. A zwitterion formulation of NTB produced a significantly greater amount of anthelminthically active ABZ metabolites (ABZ and ABZSO) than a trisamine salt formulation of the same compound. Although there was no difference in the total amount of products formed, both cattle ruminal and ileal fluids showed a greater oxidative capacity than sheep derived fluids. This was evidenced by the greater amounts of ABZSO recovered and by the resultant lower ratios of ABZ/ABZSO obtained with cattle fluids.