Analytical and metabolic studies of the trypanocidal diamidines

• Main Author: Atsriku, Christian
• Published: University of Strathclyde 2002
• Subjects: 615; Drug resistance
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273776

Following the expiry of patent protection of the innovator product Berenil®, there has been an influx of substandard generic substitutes of the veterinary trypanocide in international commerce, which have been implicated as being a major contributor to the emergence of drug resistance. This situation has necessitated the development of analytical techniques, which would help safeguard the quality and efficacy of generic formulations of diminazene. A selective, accurate, precise and simple reverse-phase isocratic HPLC method for the simultaneous assay of diminazene aceturate and antipyrine (excipient) in pharmaceutical formulations has been developed and validated. The degradation and manufacturing impurities of diminazene have been identified by electrospray ionization mass spectrometry and characterized by NMR spectroscopy of the synthetic compounds. The developed method has been applied for the quality evaluation of over one hundred generic samples of diminazene obtained from Sub -Saharan Africa. The results give an indication that the quality of generic formulations of diminazene on the African market is compromised. Changes in the metabolism of a drug can lead to altered pharmacokinetics, resulting in an increase or decrease in drug plasma concentration, leading to toxification or therapeutic failure. The metabolism of diminazene and pentamidine in isolated rat and pig hepatocytes have been investigated. Diminazene was not metabolized in either rat or pig hepatocytes. While there were no obvious qualitative differences in the metabolic profiles of pentamidine in either of the animals, the rate of metabolism in rats appeared to be faster. Pretreatment of rats with either 3-methylcholanthrene (3-MC), phenobarbitone (PB) or deltamethrin (DM) caused inhibition of pentamidine metabolism to different extents. There were significant differences between the profiles of the three major metabolites of pentamidine in DM and 3-MC pretreated rats compared to the control group, whereas etreatment with PB did not result in any significant changes in profiles of metabolites.