David W. Fink

Pharmacokinetic studies of ivermectin: Effects of formulation

Studies are reported which describe the effects of formulation, animal species, and route of administration on the pharmacokinetics of ivermectin. Biological half-life t1/2 increases in the order: swine (0.5 day) > dogs (1.8 day) > cattle ≌ sheep (2.8 day). Formulation modifications, based upon the solubility properties of the drug, have been directed towards the development of a nonaqueous injectable formulation for cattle and an aqueous vehicle for horses. Bioavailability following subcutaneous injection in cattle can be regulated by control of injection solvent composition: a vehicle composed of a mixed aqueous-organic solvent exhibits pharmacokinetic properties (i.e., Cp, t1/2, AUC, and F) intermediate between those furnished by an aqueous formulation and via a purely nonaqueous solvent. The longer apparent biological half-life from this latter vehicle (t1/2=8.3 days) confirms that a slow absorption process dominates the pharmacokinetics in the nonaqueous injectable product to produce an effective controlled-release formulation. These bioavailability results illustrate the increase in the concentration of an organic solvent and a concomitant decrease in surfactant concentration in a micellar aqueous system for prolonged drug delivery via injection.

Pharmacokinetics of ivermectin in animals and humans

The pharmacokinetic properties of ivermectin are a function of the species in which the compound is studied. Ivermectin is effective against parasites in a wide variety of hosts—including cattle, sheep, dogs, swine, and horses. A previous review of ivermectin has described the effects of formulation and route of administration on its pharmacokinetic properties in animals (Lo et al. 1985). That publication included examples of formulation modifications directed toward the development of oral and parenteral dosage forms; it also illustrated the use of drug plasma concentrations for characterizing the drug and for modifying formulations for specific efficacy. The following summary presents the results of representative pharmacokinetic and bioavailability studies of this drug in different animal species and in humans. It includes descriptions of the experimental procedures as well as the various measurement techniques used in these studies to describe the pharmacokinetic properties of ivermectin.

Determination of avermectins in plasma at nanogram levels using high-performance liquid chromatography with flourescence detection

An analytical method is described for the determination of the avermectins in plasma based upon high-performance liquid chromatography of fluorescent derivatives of these compounds. The analyte is isolated by adsorption chromatography on Florisil, dehydrated in an acetic anhydride-pyridine mixture, and the fluorophore is further separated by chromatography on silica gel in advance of introduction into a reversed-phase system. This method, which can be applied to samples containing as little as 0.2 ng drug per ml, has an accuracy of 5% mean relative error and a precision of 8% relative standard deviation. A study and discussion of several factors which affect the analytical reaction are included.

Discovery of the Development Candidate N-tert-Butyl Nodulisporamide: A Safe and Efficacious Once Monthly Oral Agent for the Control of Fleas and Ticks on Companion Animals

Nodulisporic acid A (1) is a structurally complex fungal metabolite that exhibits systemic efficacy against fleas via modulation of an invertebrate specific glutamate-gated ion channel. In order to identify a nodulisporamide suitable for monthly oral dosing in dogs, a library of 335 nodulisporamides was examined in an artificial flea feeding system for intrinsic systemic potency as well as in a mouse/bedbug assay for systemic efficacy and safety. A cohort of 66 nodulisporamides were selected for evaluation in a dog/flea model; pharmacokinetic analysis correlated plasma levels with flea efficacy. These efforts resulted in the identification of the development candidate N-tert-butyl nodulisporamide (3) as a potent and efficacious once monthly oral agent for the control of fleas and ticks on dogs and cats which was directly compared to the topical agents fipronil and imidacloprid, with favorable results obtained. Multidose studies over 3 months confirmed the in vivo ectoparasiticidal efficacy and established that 3 lacked overt mammalian toxicity. Tissue distribution studies in mice using [(14)C]-labeled 3 indicate that adipose beds serve as ligand depots, contributing to the long terminal half-lives of these compounds.

Evolution of a specific fluorogenic derivatization of ivermectin for bioanalytical applications. A review

The evolution of the fluorogenic derivatization of ivermectin is traced through a series of continual modifications that have resulted in improvements in speed and sensitivity. Since the original development of this selective analytical technique, the reaction time has been shortened from 24 h at 100 degrees C to < 30 s at room temperature and, through modifications of the derivatization reagent and catalyst, the sensitivity has also been increased 50-fold to 20 pg of analyte with no significant decrease in precision. A procedure is reported, based on the use of fluorescence derivatization, which eliminates the use of solid-phase columns for sample preparation and fluorophore isolation, and is faster and less cumbersome than previous methods. The method was evaluated with cattle and canine plasma samples over the concentration range 1.0-40 ng ml-1 of ivermectin. It has an accuracy of 1.9% (mean relative error) over this concentration range and a precision of 5.6% (RSD) at the 1 ng ml-1 ivermectin concentration level in a 1 ml plasma sample.

The electronic spectral properties of gallic acid

Abstract The electronic spectral properties of gallic acid (3,4,5-trihydroxybenzoic acid), a chemiluminescence reagent which is unstable in oxygenated aqueous solution, have been determined under conditions regulated to retard decomposition. The characteristic blue and red shifts in the u.v. absorption spectra which accompany carboxyl and phenol dissociation, respectively, are in accord with the trends usually observed for these functional groups. The dianionic species exhibits a fluorescence emission band with a peak at 370 nm under 300-nm excitation.

Determination of ivermectin in feeds by high-performance liquid chromatography

A direct high-performance liquid chromatographic method has been developed for the determination of ivermectin in feeds over the concentration range 50–500 mg kg–1. Sample preparation is based upon extraction into methanol and separation of interferences on a gravity-fed alumina (activity III) column in advance of introduction into a standard reversed-phase chromatographic system. Experiments are described to document the efficiency of this sample preparation scheme and the chemical yield of the analyte through the process. The method has been applied to three types of feed samples with an accuracy of ±3.4% mean relative error and a relative standard deviation (precision) of <3%. It has a lower limit of detection with a signal to noise ratio 2 : 1 of 6.0 mg kg–1 of ivermectin.

Spectrophotometric quantification of the salicylanilide anthelmintic rafoxanide based on the charge-transfer absorbance of its iron(III) complex

Abstract Formation of an iron(III)—rafoxanide chelate provides the basis for a direct spectrophotometric method for the quantification of this halogenated salicylanilide in the concentration range 9.00 × 10 -4 –7.00 × 10 -3 M. The intense visible charge-transfer absorption band of the complex at 505 nm represents a general spectrophotometric characteristic that is useful for other substituted salicylanilides. The maximum absorption wavelength of the charge-transfer band shifts monotonically to higher energy in an order consistent with Hammett substituent constants.