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2013-06-30 - Colloque/Présentation - poster - Anglais - 1 page(s)

Hambye Stéphanie , Stanicki Dimitri , Vanden Eynde Jean-Jacques, Blankert Bertrand , "Development and validation of liquid chromatography (LC) methods for the determination of pentamidine and new analogs in rat plasma and urine" in 24th International Symposium on Pharmaceutical and Biomedical Analysis, Bologne, Italie, 2013

  • Codes CREF : Chimie analytique (DI1314), Pharmacocinétique (DI3431), Sciences pharmaceutiques (DI3400), Techniques séparatives (DI2729)
  • Unités de recherche UMONS : Analyse pharmaceutique (M130), Chimie organique (S836)
  • Instituts UMONS : Institut des Sciences et Technologies de la Santé (Santé)

Abstract(s) :

(Anglais) Pentamidine (PTMD) isethionate (Fig. 1, 1), an aromatic diamidine derivative, is an antiprotozoal agent used in different parasitic diseases as Pneumocystis Jirovicii Pneumonia [1]. Recently, PTMD has also been described as a potential active agent in myotonic dystrophy [2]. Figure 1 - Structures of PTMD (1) and analogs (2-3) Unfortunately, this agent is also well known for its toxicity. Nowadays, the synthesis of new drugs with less adverse effects than PTMD, without reduction of efficacy, is still very challenging. The laboratory of Organic Chemistry in the University of Mons has synthesized a variety of new PTMD analogs. After in vitro testing (on pneumocystis cultures), two of them (Fig. 1, 2-3) with favorable results were selected for in vivo studies and pharmacokinetic evaluation. These kinds of studies need efficient and sensitive analytical methods in order to quantify the reference drug (PTMD) and the new compounds in biological fluids. We have first developed a reproducible reversed-phase high performance liquid chromatography (HPLC) method with ultraviolet (UV) detection with a pre-extraction step [4]. PTMD is extracted from rat plasma through a solid phase extraction (SPE) HLB (hydrophilic lipophilic balanced) cartridge, while analogs were extracted from plasma by protein precipitation using acetonitrile. The limits of detection of PTMD, 2 and 3 were 29.6, 74.2 and 70.9 ng free drug/ml plasma respectively. These methods were successfully validated by an original approach using accuracy profiles based on tolerance interval for the total error measurement [5]. These methods allow the creation of preliminary pharmacokinetic profiles. Nevertheless the limits of detection is a little high for the purpose and some difficulties appear when we tried to apply these methods in another biological matrix, urine, to complete the data of pharmacokinetic. Ultra High Performance Chromatography (UPLC) methods with fluorescence detection are currently in development for the same compounds in both plasma and urine with a different preextraction step using SPE WCX cartridges. A limit of detection of 1 ng/ml for PTMD is expected with a time of analysis of 4 min, 5 fold less than for HPLC. UPLC methods will be validated with the same protocol. To our knowledge, it will be the first time that a UPLC method is developed for PTMD.