The effect of variations in urinary pH on the pharmacokinetics of diethylcarbamazine.

Edwards, G.; Breckenridge, AM; Adjepon-Yamoah, K. K.; Orme, ML; Ward, SA

doi:10.1111/j.1365-2125.1981.tb01311.x

Cited by 31 publications

(14 citation statements)

References 8 publications

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“…Additionally, the terminal 79 elimination half-life of diethylcarbamazine and area under the plasma concentration-time curve AUCO-oc,) were significantly greater at alkaline pH than under acidic conditions (figs 5, 6). The proportion of diethylcarbamazine excreted as the Noxide metabolite was not affected by urinary pH (Edwards et al 1981c). …”

Section: Pharmacokineticsmentioning

confidence: 94%

Clinical Pharmacokinetics of Anthelmintic Drugs

Edwards

Breckenridge

1988

Clinical Pharmacokinetics

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A rational strategy for chemotherapy demands that dosage schedules be based on an adequate knowledge of clinical and biochemical pharmacology. Many anthelmintic drugs (e.g. suramin, diethylcarbamazine, hycanthone) were introduced before modern techniques for drug evaluation (controlled clinical trials) and before the development of specific and sensitive analytical methods for the assay of drugs and metabolites in biological fluids. Thus, many of the regimens used today for the treatment of parasitic diseases are largely empirically derived. By means of specific analytical methodology (high performance liquid chromatography, gas chromatography and mass-spectrometry) introduced in the 1960s, it is now possible to measure drugs and their metabolites with specificity and sensitivity. Much of this review deals with compounds which are active against the major systemic helminths, i.e., filariae (diethylcarbamazine, ivermectin and suramin) and schistosomes (niridazole, metrifonate, oxamniquine and praziquantel), but recent advances in the treatment of hydatid disease involving the benzimidazole carbamates albendazole and mebendazole are also discussed. Among the imidazole derivatives, mebendazole, a broad-spectrum anthelmintic, is poorly absorbed from the gastrointestinal tract after a therapeutic dose, but that fraction which is absorbed and escapes hepatic first-pass extraction is pharmacologically active against systemic helminths. Albendazole is more completely absorbed, but is almost undetectable in plasma due to its rapid conversion to an active sulphoxide metabolite. This compound may well become the drug of choice for the chemotherapy of echinococcosis. Levamisole, the 1-isomer of tetramisole, is rapidly and completely absorbed, but has not been widely used in systemic helminthiases because of severe side effects associated with prolonged dosage. Diethylcarbamazine is microfilaricidal against Onchocerca volvulus, but its use has been associated with major adverse effects resulting from its action on the microfilariae. These effects are related to the concentration of the drug in the plasma which, in turn, is influenced by urinary pH. The elimination half-life of diethylcarbamazine is prolonged and renal clearance reduced in alkaline urine. Under these conditions the microfilaricidal effect is enhanced, but the adverse reactions to treatment are more severe. Suramin is the only available antifilarial agent with macrofilaricidal activity. It has a long elimination half-life (36 to 54 days), and is highly (99.7%) bound to plasma protein which limits its removal from the blood.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Pharmacokineticsmentioning

confidence: 94%

Clinical Pharmacokinetics of Anthelmintic Drugs

Edwards

Breckenridge

1988

Clinical Pharmacokinetics

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“…Although the dose of sodium bicarbonate used in this study was less than that employed by Edwards et al (1981a) the urine in the bicarbonate treated patients was maintained at a relatively alkaline pH. The smaller dose of sodium bicarbonate was chosen for reasons of patient acceptability and convenience of administration.…”

Section: Discussionmentioning

confidence: 99%

“…In the volunteer study of Edwards et al (1981a), however, the administration of bicarbonate was continued throughout the sampling period.…”

Section: Discussionmentioning

confidence: 99%

“…The selection of an optimum dose schedule for DEC might be assisted by knowledge of its clinical pharmacology. Edwards et al (1981a) have shown that the plasma half-life of DEC after a single oral dose is significantly prolonged when an alkaline urine is maintained as compared to the situation when an acidic urine is produced. They suggested that with manipulations of urinary pH smaller doses of DEC might be utilised thus decreasing the total body load of the drug.…”

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confidence: 99%

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The effect of moderate urine alkalinisation on low dose diethylcarbamazine therapy in patients with onchocerciasis.

Awadzi¹,

Adjepon-Yamoah²,

Edwards³

et al. 1986

Brit J Clinical Pharma

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1 Twenty-one patients with moderate to heavy infections with 0. volvulus were treated with 25 mg of diethylcarbamazine (DEC) citrate twice daily for 10 days. In 11 patients the urine was made alkaline with sodium bicarbonate, 2 g, administered 6 hourly for three doses daily beginning 1 day before DEC was started and continued throughout the DEC therapy. Ten patients served as controls. 2 The mean pre-dose plasma DEC concentration during treatment and the mean plasma DEC half-life were significantly higher in bicarbonate treated patients as compared to controls. Total urinary excretion of DEC was significantly less in the bicarbonate treated group than in controls. 3 Mean overall total reaction was higher in bicarbonate-treated patients but the difference was not significant. 4 The bicarbonate-treated group achieved a significantly greater reduction in skin microfilarial counts than the control group as assessed 1 week after completion of therapy, but there was little difference at 1 month. Microfilarial killing was associated with microfilarial mobilisation, alteration in peripheral leucocytes and elevation in serum aminotransferases in both groups. 5 There was no effect of DEC on the number of adult worms recovered in nodules removed at the end of the therapy. 6 This study indicates that moderate urinary alkalinisation alters the kinetics of DEC and the therapeutic response. However the severity of clinical reaction coupled with the inadequate level of microfilarial killing achieved make it unlikely that manipulation of urinary pH will be of practical value in onchoceriasis chemotherapy.

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“…DEC is readily absorbed and stable throughout gastrointestinal tract (GIT) (8). Plasma t 1/2 of DEC varies from 4 to 12 h depending upon urinary pH which requires frequent dosing of DEC (9). Mean resident time of DEC in blood can be increased either by preparing its sustained release formulation or by increasing urinary pH; the later task, however, is neither convenient nor clinically safe.…”

Section: Introductionmentioning

confidence: 99%

Floating Elementary Osmotic Pump Tablet (FEOPT) for Controlled Delivery of Diethylcarbamazine Citrate: a Water-Soluble Drug

2011

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Abstract. The present work investigates the feasibility of the design of a novel floating elementary osmotic pump tablet (FEOPT) to prolong the gastric residence of a highly water-soluble drug. Diethylcarbamazine citrate (DEC) was chosen as a model drug. The FEOPT consisted of an osmotic core (DEC, mannitol, and hydrophilic polymers) coated with a semipermeable layer (cellulose acetate) and a gas-generating gelling layer (sodium bicarbonate, hydrophilic polymers) followed by a polymeric film (Eudragit RL 30D). The effect of formulation variables such as concentration of polymers, types of diluent, and coat thickness of semipermeable membrane was evaluated in terms of physical parameters, floating lag time, duration of floatation, and in vitro drug release. The Fourier transform infrared and X-ray diffraction analysis were carried out to study the physicochemical changes in the drug excipients powder blend. The integrity of the orifice and polymeric film layer was confirmed from scanning electron microscopy image. All the developed FEOPT showed floating lag time of less than 8 min and floating duration of 24 h. A zero-order drug release could be attained for DEC. The formulations were found to be stable up to 3 months of stability testing at 40°C/75% relative humidity.

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The effect of variations in urinary pH on the pharmacokinetics of diethylcarbamazine.

Cited by 31 publications

References 8 publications

Clinical Pharmacokinetics of Anthelmintic Drugs

Clinical Pharmacokinetics of Anthelmintic Drugs

The effect of moderate urine alkalinisation on low dose diethylcarbamazine therapy in patients with onchocerciasis.

Floating Elementary Osmotic Pump Tablet (FEOPT) for Controlled Delivery of Diethylcarbamazine Citrate: a Water-Soluble Drug

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