Pharmacokinetics of amoxicillin in skin following iontophoretic administration in a rabbit model.

摘要

The purpose of this thesis was to study the pharmacokinetics of amoxicillin in skin following iontophoretic administration by using a stainless-steel patch.;FDA labeled indication of amoxicillin includes treatment of skin infections. The pharmacokinetic behavior of amoxicillin (AMX) in skin is poorly studied. It has been observed that amoxicillin is used for anthrax and treats skin or soft tissue infection, cutaneous bacillus anthracis and bacterial Infection caused by susceptible Streptococcus (alpha- or beta-hemolytic strains only), Staphylococcus, or Escherichia coli . Ciprofloxacin or doxycycline is the initial drug of choice for postexposure prophylaxis following a suspected or confirmed bioterrorism-related anthrax exposure whereas amoxicillin is an alternative for postexposure prophylaxis of anthrax following exposure to aerosolized bacillus anthracis spores (inhalational anthrax). Amoxicillin is also an alternative for treatment of cutaneous anthrax.;Iontophoresis is a penetration enhancer technique that uses a mild electrical current to increase the penetration of charged ions through the skin. Since AMX is ionized at physiological pH it looks a suitable candidate for iontophoretic delivery. Skin concentrations were monitored via microdialysis sampling.;Microdialysis is a semi-invasive separation technique that allows the sampling or the delivery of molecules in vivo, according to the concentration gradient between the solution perfusing the probe and the extracellular fluid surrounding it. Owing to selective access to the target site for most anti-infective drugs, microdialysis satisfies regulatory requirements for pharmacokinetic distribution studies and has become a reference technique for tissue distribution studies.;The HPLC method selected and validated for the determination of amoxicillin in microdialysis samples consisted of a reversed phase C18 column, flow rate of 1 ml/min and a detection wavelength of 230 nm. Mobile phase used for microdialysis consisted of 90% 50mM phosphate buffer (pH=3) containing 0.1% triethylamine and 10% methanol. The retention time was 3.93 min. The calibration curves for microdialysis samples were linear in the range of 0.1 to 100 1.1.g/m1 with a correlation coefficient larger than 0.99. The lower limit of quantification (LLOQ) was 0.1 microg/ml.;The kinetics of amoxicillin was investigated in 3 female pathogen-free New Zealand albino rabbits. Microdialysis probes were implanted into the upper dorsal shaved skin of a tranquilized rabbit and perfused with lactated ringer's solution. Patches donated by Dr. Phillip Friden (Transport Pharmaceuticals, Framingham, MA) were used to deliver amoxicillin for 1 hour at different current densities (100, 200, and 300/cm2) on different occasions in a randomized cross-over experimental design in same dose. Microdialysis samples were collected at selected time intervals. Retrodialysis was performed at the start of each experiment to assess probe recovery and correct the dialysate concentration to reflect the actual interstitial fluid concentration.;The results show that measurable amoxicillin concentrations were reached immediately after the onset of the current in the skin. Though there was no considerable difference in Cmax and AUC across the different current densities, this study indicates the possibility of transdermal delivery of amoxicillin by iontophoresis.