Theophylline disposition—effects of cimetidine, mebendazole and albendazole

On the basis of the report that benzimidazoles bind to and inhibit the hepatic cytochrome P-450 enzyme system, the effect of mebendazole and albendazole on theophylline disposition was studied in 12 volunteers. Mebendazole at a dose of 100 mg b.d. for 3 days did not significantly alter the theophylline half-life, volume of distribution or clearance in a group of six. In another group of six adult volunteers, albendazole (400 mg) pretreatment did not alter the same parameters. However, in this second group, pretreatment with cimetidine (400 mg t.d.s. for 5 days) significantly increased theophylline half life from 7.7 to 9.8 +/- 1.5 h (P less than 0.001) and reduced its clearance from 0.8 to 0.60 +/- 0.1 ml min-1 kg-1 (P less than 0.005). The volume of distribution was not altered significantly. It is concluded that at therapeutic doses it is unlikely that mebendazole or albendazole will induce theophylline toxicity if co-administered with the bronchodilator. Cimetidine-induced impairment of theophylline metabolism is such that toxicity will be more likely in individuals with initial high theophylline clearance.     

Selective inhibition of drug oxidation after simultaneous administration of two probe drugs,antipyrine and tolbutamide

Summary The effects of sulphaphenazole, cimetidine and primaquine on the disposition of antipyrine and tolbutamide in healthy volunteers have been investigated. The model substrates were administered simultaneously in order more clearly to define any selective effects of the potential inhibitors. Sulphaphenazole produced a significant increase in the half-life of tolbutamide (7.10 to 21.50 h) and a correponding decrease in its clearance (0.260 to 0.084 ml·min^–1·kg^–1). Clearance to hydroxytolbutamide (OHTOL) and carboxytolbutamide (COOHTOL) was also significantly decreased.In contrast, sulphaphenazole had no effect on the disposition of antipyrine. Administration of cimetidine did not significantly alter the disposition of either model drug. However, a 1.6-times higher dose of cimetidine did increase the half lives both of tolbutamide and antipyrine (6.21 to 9.04 h and 14.2 to 19.2 h, respectively) and decrease their clearance (0.226 to 0.148 and 0.50 to 0.31 ml·min^–1 kg^–1, respectively). Clearance to OHTOL and hydroxymethylantipyrine (HMA) was reduced.A single dose of primaquine had no demonstrable effect on tolbutamide disposition whereas the half-life of antipyrine was increased (12.1 to 15.0 h) and its clearance decreased (0.63 to 0.38 ml·min^–1·kg^–1). The partial clearance to HMA, 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) was also significantly reduced.The two main inferences are first, that tolbutamide and antipyrine are metabolished by different forms of cytochrome P-450, and second that a battery of model substrates is needed to investigate the inhibitory effects of a drug in man.     

Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and mebendazole: an interaction study in healthy volunteers

Background  

Benzimidazoles are often used concomitantly with protease inhibitors in patients with helminthic disease and HIV infection. Low bioavailability and extensive first-pass metabolism make benzimidazoles prone to pharmacokinetic drug interactions. The aim of the present study was to investigate potential drug interactions between the benzimidazoles albendazole and mebendazole and the potent CYP3A4 inhibitor ritonavir.     

Activities of fenbendazole in comparison with albendazole against Echinococcus multilocularis metacestodes in vitro and in a murine infection model

The current chemotherapeutic treatment of alveolar echinococcosis (AE) in humans is based on albendazole and/or mebendazole. However, the costs of treatment, life-long consumption of drugs, parasitostatic rather than parasiticidal activity of chemotherapy, and high recurrence rates after treatment interruption warrant more efficient treatment options. Experimental treatment of mice infected with Echinococcus multilocularis metacestodes with fenbendazole revealed similar efficacy to albendazole. Inspection of parasite tissue from infected and benzimidazole-treated mice by transmission electron microscopy (TEM) demonstrated drug-induced alterations within the germinal layer of the parasites, and most notably an almost complete absence of microtriches. On the other hand, upon in vitro exposure of metacestodes to benzimidazoles, no phosphoglucose isomerase activity could be detected in medium supernatants during treatment with any of these drugs, indicating that in vitro treatment did not severely affect the viability of metacestode tissue. Corresponding TEM analysis also revealed a dramatic shortening/retraction of microtriches as a hallmark of benzimidazole action, and as a consequence separation of the acellular laminated layer from the cellular germinal layer. Since TEM did not reveal any microtubule-based structures within Echinococcus microtriches, this effect cannot be explained by the previously described mechanism of action of benzimidazoles targeting β-tubulin, thus benzimidazoles must interact with additional targets that have not been yet identified. In addition, these results indicate the potential usefulness of fenbendazole for the chemotherapy of AE.     

Activity of metronidazole, azithromycin and three benzimidazoles on Giardia lamblia growth and attachment to a human intestinal cell line

Background: Attachment of Giardia lamblia trophozoites to enterocytes is essential for colonization of the small intestine and is considered a prerequisite for Giardia-induced enterocyte damage. Inhibition of attachment may therefore have therapeutic potential Methods: Enterocyte-like differentiated Caco-2 cells were used as a biologically appropriate attachment surface to determine the effect of three benzimidazole compounds (albendazole, mebendazole and thiabendazole), azithromycin and metronidazole on Giardia attachment. The results were compared with the ability for each drug to inhibit Giardia growth, measured using [³H]-thymidine uptake. Results: The benzimidazoles inhibited Giardia attachment at much lower concentrations than did metronidazole. However, metronidazole was a much more potent inhibitor of growth than any of the benzimidazoles. Azithromycin did not significantly impair Giardia attachment or growth. The benzimidazoles decrease attachment but are less giardiacidal than metronidazole. Conclusion: This model appears useful for testing potential antigiardial compounds and investigating mechanisms of drug action.     

Efficacy of alebendazole and mebendazole in the treatment of Ascaris and Trichuris infections

This study was conducted to evaluate the efficacy of 100 mg mebendazole administered twice a day for three consecutive days and a single dose of 400 mg albendazole for the treatment of single or mixed Ascaris lumbricoides and Trichuris trichiura infections. Both drugs were found to be highly effective against Ascaris lumbricoides infection, with cure rate of over 96% and egg reduction of over 99.8%. However, the efficacy of the two drugs against Trichuris trichiura infection was low. Mebendazole appeared to be more effective against Trichuris trichiura in that it exhibited a cure rate of 34.7% and egg reduction of 92.3% as opposed to albendazole, which exhibited a cure rate and egg reduction rate of 13.9% and 63.4%, respectively. The two drugs appeared to have little effect on Schistosoma mansoni infection. More complaints were reported by individuals treated with albendazole than with mebendazole. In conclusion, mebendazole appears to be safer and more effective for the treatment of single or mixed infections with Trichuris trichiura and Ascaris lumbricoides as compared to albendazole.     

Chromatographic isolation and mass spectrometric identification of a base-induced mebendazole fluorophor

Sodium hydroxide treatment of the benzoylbenzimidazole anthelmintics mebendazole and flubendazole produces yellow solutions that possess practically no fluorescence characteristics under various conditions. However, when spotting the alkaline solutions on filter paper and examining the spots under U.V., strong bluish-white fluorescence is obtained. When pouring liquid nitrogen over the spots, a very intense bluish-white fluorescence followed by a long-lasting greenish phosphorescence is observed. These luminescence phenomena allow visualization of 1 ng of mebendazole and of 5 ng of flubendazole per spot. A preparative separation by means of column liquid chromatography was worked out for the isolation of the fluorophor in case of mebendazole. Combined spectroscopic methods indicated the formation of a primary amine function in position 2 of the imidazole nucleus by hydrolytic cleavage of the -NH-CO-bond. A discussion on the mechanism of fluorescence is given.     

Liquid chromatography with electrochemical detection for monitoring mebendazole and hydroxymebendazole in echinococcosis patients

A sensitive method is described for the simultaneous determination of mebendazole and hydroxymebendazole using flubendazole as an internal standard. The analytes were isolated with a single chloroform extraction from 1.0 ml of alkalinized plasma or cyst liquid samples. Separation and quantitation were performed with high-performance liquid chromatography with electrochemical detection. The limit of detection for mebendazole and hydroxymebendazole was approximately 5 and 2.5 ng/ml, respectively. The accuracy of the method was confirmed for mebendazole by a good correlation with an existing radioimmunoassay method. The method was applied for monitoring mebendazole therapy in echinococcosis patients. The results presented support the necessity of such monitoring, as most of the observed peak plasma concentrations did not reach the level regarded as minimal for therapeutic effect.     

Differential efficacy of mebendazole and albendazole againstNecator americanus but not forTrichuris trichiura infestations

Summary The effect of single oral doses of albendazole 600 mg and mebendazole 1 g given to 56 and 60 men, respectively, withT. trichiura and/orN. americanus infestation has been studied. Both albendazole and mebendazole cured more than 90% ofT. trichiura infestations, but only albendazole (95%) and not mebendazole (21%) had a high cure rate forN. americanus infestations. Thus, albendazole is the preferred benzimidazole derivate for the mass treatment of subjects withT. trichiura and/orN. americanus infestations.     

The effect of acute withdrawal from cigarette smoking on indocyanine green and antipyrine clearance

The effects of acute withdrawal from cigarette smoking on indocyanine green (ICG) clearance and antipyrine pharmacokinetics were studied in healthy young male volunteers. Two separate crossover clinical trials, each using 12 subjects, were used to compare the disposition of the drugs from 24 to 36 hours after withdrawal to the disposition found under control conditions. The median difference of ICG clearance and all antipyrine pharmacokinetic parameters from smoking control was less than 13%, indicating that short-term smoking withdrawal had no effect large enough to be of clinical significance on hepatic blood flow or hepatic drug-metabolizing capacity. Rates of hepatic blood flow were normal in comparison with values published for larger sample populations. The lack of any clinically significant effect of smoking withdrawal on hepatic blood flow or on the disposition of antipyrine, a drug with very low hepatic extraction, indicates that on a pharmacokinetic basis, changes in dosage regimens for most drugs are not necessary on acute withdrawal from smoking.     

Changes in the disposition of promethazine during multiple dosing in the rabbit

During a multiple dosing regimen, the area under the promethazine blood concentration-time profile progressively decreased indicating auto-induction of metabolism. The increase in promethazine clearance (mean 35%) was not reflected in changes in either elimination half-life or minimum blood concentrations during the dosing interval. This was attributed to a deep compartment in the disposition of promethazine in the rabbit. The changes in promethazine clearance were accompanied by proportionally larger changes in the clearance of the monodesmethylpromethazine metabolite. The effect of promethazine pretreatment on the clearance of antipyrine was also studied and was found to be significantly increased by a mean of 17% following pretreatment with promethazine. However, the changes in the clearance of antipyrine did not highly correlate with those of promethazine and monodesmethylpromethazine. This may indicate that promethazine induces metabolic systems in the rabbit for which antipyrine is not a good substrate.     

Effects of methimazole on the kinetics of netobimin metabolites in cattle.

1. The effects of methimazole (MTZ) on the pharmacokinetic behaviour of netobimin (NTB) and its albendazole (ABZ) metabolites were studied in calves. NTB trisamine salt solution was given by subcutaneous (12.5 mg/kg) and oral (20 mg/kg) routes, either alone or co-administered with MTZ (1.5 mg/kg, intramuscularly). 2. NTB parent drug was detected only after s.c. treatments, showing rapid absorption, early Cmax and fast disposition. ABZ was not found in plasma at any time after either s.c. or oral treatments. 3. Concomitant treatment with MTZ significantly increased the albendazole sulphoxide (ABZSO) elimination half-life (t1/2 beta) (321%) and mean residence time (MRT) (170%) from the values obtained after s.c. treatment with NTB alone. 4. Oral treatment resulted in an ABZSO pharmacokinetic profile with an AUC 27% higher, a significantly longer t1/2 beta (151%) and MRT (124%) in the presence of MTZ. 5. We conclude that when co-administered with NTB in cattle, MTZ induces significant changes in the disposition kinetics of the anthelmintically active ABZSO metabolite.     

Effect of chlormethiazole on hepatic monooxygenases activity in vivo

Summary Chlormethiazole is a strong inhibitor of cytochrome P-450-dependent monooxygenases in isolated human liver microsomes. To assess its effect in vivo, we measured the pharmacokinetic parameters of antipyrine (1.2 g orally) and tolbutamide (0.5 g i. v.) before and after administration of chlormethiazole 314 mg b. d. for 2 days to 8 healthy volunteers.The elimination of neither substance was affected, indicating that chlormethiazole did not inhibit in vivo the cytochrome P-450 isozymes responsible for the elimination of antipyrine and tolbutamide.     

Assessment of enzyme induction and enzyme inhibition in humans: toxicological implications

1. The principal methods used for the assessment of enzyme induction and enzyme inhibition are measurement of the pharmacokinetics of a model compound (probe drug), analysis of drug metabolism in vitro, and determination of changes in the disposition of, and endogenous substrate for, the enzyme of interest. 2. Probe drugs that have been used for this purpose include antipyrine, aminopyrine, tolbutamide, caffeine, theophylline, warfarin, oxazepam and paracetamol. Measurement of the excretion of metabolites of cortisol and oestradiol, which are endogenous substrates for cytochrome P450 IIIA enzymes, provides a non-invasive means of assessing enzyme induction or inhibition. 3. Combined pharmacokinetic/pharmacodynamic studies are required to assess the pharmacological relevance of either induction or inhibition of the enzymes involved in drug metabolism. 4. At present it is difficult to assess the toxicological implications of enzyme induction and inhibition in man. Safe probe drugs are required for the enzymes primarily responsible for drug detoxication, such as epoxide hydrolase and glutathione transferase, in order to identify individuals particularly at risk.     

Effects of CYP2C19 and CYP2C9 genetic polymorphisms on the disposition of and blood glucose lowering response to tolbutamide in humans

Several recent in-vitro data have revealed that CYP2C19, in addition to CYP2C9, is also involved in the 4-methylhydroxylation of tolbutamide. We evaluated the relative contribution of CYP2C9 and CYP2C19 genetic polymorphisms on the disposition of blood glucose lowering response to tolbutamide in normal healthy Korean subjects in order to reappraise tolbutamide as a selective in-vivo probe substrate of CYP2C9 activity. A single oral dose of tolbutamide (500 mg) or placebo was administered to 18 subjects in a single-blind, randomized, crossover study with a 2-week washout period. Twelve subjects (of whom six were CYP2C19 extensive metabolizer (EM) and six were CYP2C19 poor metabolizer (PM) genotype) were of the homozygous wild-type CYP2C9*1 genotype; the other six subjects were of the CYP2C9*1/*3 and CYP2C19 EM genotype. Pharmacokinetic parameters were estimated from plasma and urine concentrations of tolbutamide and 4-hydroxytolbutamide. Serum glucose concentrations were measured before and after oral intake of 100 g dextrose. In subjects heterozygous for the CYP2C9*3 allele, C(max) and AUC of tolbutamide were significantly greater and the plasma half-life significantly longer than those in homozygous CYP2C9*1 subjects. No pharmacokinetic differences were found between CYP2C19 EM and PM genotype subjects. The estimated AUC of the increase in serum glucose after oral intake of 100 g dextrose was 2.7-fold higher in subjects with the wild-type CYP2C9 genotype than in those with CYP2C9*1/*3, but CYP2C19 genetic polymorphism did not alter the blood glucose lowering effect of tolbutamide. The plasma AUC of 4-hydroxytolbutamide and the ratio of 4-hydroxytolbutamide/tolbutamide did not differ significantly between CYP2C19 PM and EM genotype subjects, while these parameters were about twice as high in subjects with the wild-type CYP2C9 genotype than in heterozygous CYP2C9*3 subjects (P < 0.05). Our results strongly suggest that the disposition and hypoglycemic effect of tolbutamide are affected mainly by CYP2C9 genetic polymorphism, but not by CYP2C19 polymorphism. The in-vivo contribution of CYP2C19 to tolbutamide 4-methylhydroxylation appears to be minor in humans. This suggests that, at least in vivo, tolbutamide remains a selective probe for measuring CYP2C9 activity in humans.     

Metabolic Cage Isolation Reduces Antipyrine Clearance in Rats

Abstract— Rats are commonly isolated individually in cages during pharmacokinetic studies. However, isolation-induced changes in drug disposition are not commonly examined. Antipyrine is a marker of hepatic oxidative function and total body water. The purpose of the study was to investigate the effect of individual housing on antipyrine pharmacokinetics. Rats were individually housed in either standard polycarbonate boxes (n = 8) or metabolic cages (n = 10). On day 1 and day 9 rats were administered a single intravenous bolus injection of antipyrine 20 mg kg^?1. Blood samples (100 μL) were obtained before and at 20, 40, 60, 90, 120, 180, 240, 300 and 360 min following the administration of the dose. Rats remained in their respective cages between evaluations. Serum antipyrine concentrations were determined by capillary electrophoresis. Pharmacokinetic parameters were estimated by model-independent methods. Antipyrine clearance was reduced by 383·4% in rats isolated in metabolic cages for eight days (P = 0·013) while the volume of distribution remained unchanged in both rat groups. These data suggest that the isolation of rats in metabolic cage systems may markedly alter the pharmacokinetics of xenobiotics, thus possibly masking experimental outcome.     

Methimazole increases the plasma concentrations of the albendazole metabolites of netobimin in sheep.

The influence of methimazole (MTZ) on the pharmacokinetics of netobimin (NTB) and its metabolites was investigated in adult sheep. NTB zwitterion suspension was administered at 20 mg kg-1 by intraruminal injection either alone or with simultaneous administration of MTZ intramuscularly at 1.5 mg kg-1. Blood samples were taken serially over a 120-h period and plasma was analysed by HPLC for NTB, albendazole (ABZ), albendazole sulphoxide (ABZSO), and albendazole sulphone (ABZSO2). NTB parent drug showed fast absorption, low area under the plasma concentration-time curve (AUC) and was rapidly removed from plasma after both treatments. The presence of MTZ did increase significantly the ABZ AUC (138 per cent) and mean residence time (MRT) (86 per cent). Concomitant treatment with MTZ resulted in a notably higher ABZSO plasma profile with significantly longer elimination half-life (t1/2 beta) (390 per cent) and MRT (252 per cent) and with significantly higher AUC (95 per cent). Also, MTZ induced significant increases in ABZSO2 t1/2 beta, AUC, and MRT. We have demonstrated a pharmacokinetic interaction between MTZ and NTB metabolites. MTZ may alter the liver biotransformation of ABZ metabolites which results in pronounced changes in the disposition kinetics of anthelmintically active metabolites.     

Effects of the benzimidazole anthelmintic drug flubendazole on rat embryos in vitro

Filarial diseases affect millions of people in poverty-stricken areas. In 2011, an investigation of the potential of flubendazole as a safe, highly efficacious, and field-usable macrofilaricidal drug was begun by Drug for Neglected Diseases initiative. As part of the preclinical development program, whole embryo culture was used to investigate the potential embryotoxicity of flubendazole and its metabolites, reduced and hydrolyzed flubendazole. Albendazole was included as a comparator. Flubendazole and albendazole showed similar potency in affecting rat embryonic development in vitro, inducing retardation of growth and dysmorphogenic effects at concentrations ≥0.5 μg/mL. The head, optic and otic systems, branchial arches and posterior body portion were affected. Diffuse areas of cell death were seen in various embryonic districts. The No Observed Effect Level (NOEL) was 0.25 μg/mL for both drugs. Reduced and hydrolyzed flubendazole were less embryotoxic than the parent compound, with NOELs 4-fold and >40-fold higher than that of flubendazole, respectively.     

Effect of single and multiple doses of sulphinpyrazone on antipyrine metabolism and urinary excretion of 6-beta-hydroxycortisol

Summary Sulphinpyrazone decreases the plasma clearance of tolbutamide and S-warfarin and increases the clearance of R-warfarin, theophylline and antipyrine. In order to determine whether sulphinpyrazone is an inducer or inhibitor or both of oxidative drug metabolism, antipyrine and its metabolites as well as 6-beta-hydroxycortisol were measured in urine before, 24 h and after 23 days of chronic administration of sulphinpyrazone (4×200 mg/day). During chronic treatment sulphinpyrazone increased the ratio of 6-beta-hydroxycortisol to the 17-hydroxycorticosteroids by 70% (p<0.02). The renal clearance of the main oxidative metabolites of antipyrine (4-hydroxyantipyrine, 3-hydroxymethylantipyrine and norantipyrine) were increased after sulphinpyrazone (p<0.02). Except for norantipyrine, no change in total excretion of antipyrine and its metabolites occurred after 24 h or after 23 days. It is concluded that sulphinpyrazone induces the enzymes which metabolize antipyrine and cortisol.     

Absence of changes in drug disposition and catecholamine sensitivity in the hyperthyroid dog.

1 In order to study the relative contribution of hepatic drug metabolizing enzymes and hepatic blood flow to the clearance of drugs in the hyperthyroid state, the disposition kinetics of two model compounds (antipyrine and propranolol) were examined in thyroid-fed dogs as compared to euthyroid and phenobarbitone-pretreated animals. 2 In hyperthyroid dogs, the possibility of catecholamine hypersensitivity was evaluated by assessing the chronotropic response to isoprenaline and by constructing a drug concentration-effect (beta-blockade) relationship. 3 The plasma propranolol half-life (0.97 +/- 0.12 h) of the hyperthyroid animals did not differ significantly from either the euthyroid group or the phenobarbitone-pretreated group. This was observed with no significant change in the apparent volume of distribution among the three experimental groups. 4 Phenobarbitone pretreatment accelerated significantly the elimination of antipyrine (half-life, 1.09 +/- 0.15 h, P less than 0.01) as compared to the euthyroid (2.84 +/- 0.35 h) and the hyperthyroid groups (2.58 +/- 0.13 h), respectively, without any changes in the apparent volume of distribution in any group. 5 Neither the chronotropic responses to exogenously administered catecholamine, nor the antagonist concentration-effect relationships support the concept that the hyperthyroid state potentiates sensitivity of the receptor-effect system of the heart. 6 The data obtained from the present study fit best with the view that thyroid hormone excess alters neither the disposition of the model compounds used nor the catecholamine-sensitivity examined.