Pharmacokinetics of cefuroxime in skin following an iontophoresis administrations in a rabbit model

The main purpose of this thesis was to study the pharmacokinetics of cefuroxime in skin following iontophoresis and to validate an HPLC method for the determination of cefuroxime in microdialysis as well as to study calibration of the microdialysis probes by retrodialysis in vitro and in vivo.;It has been said and observed that cefuroxime, a second generation cephalosporin, has dermatological effect. FDA recommends that it can be used in the Uncomplicated Skin and Skin-Structure Infections caused by Staphylococcus aureus (including beta-lactamase-producing strains) or Streptococcus pyogenes. However, there is no such evidence of cefuroxime being a promising drug for skin disease and there is no topical or transdermal preparation of cefuroxime in the market. The main purpose of my thesis was to find out whether the cefuroxime can be administered by iontophoresis and can reach up to effective concentration against the Staphylococcus aureus or Streptococcus pyogenes. If the concentration in the skin reaches to MIC (Minimum Inhibitory Concentration) then there are chances that drug may have further dermatological action. The MIC of cefuroxime in the skin is 0.5 to 2.0 mug/m1 for the infection cause by Staphylococcus aureus and Streptococcus pyogenes. To monitor target site concentrations in animals and humans, several techniques have been employed such as biopsies, saliva and skin blister fluid sampling, imaging techniques, and microdialysis. In contrast to microdialysis, which allows sequential sampling over time, traditional concentration measurements in bodily secretions or biopsy samples usually only yield a limited number of time points.;Microdialysis is a semi-invasive sampling technique. It has been employed for the in vivo measurement of antibiotic tissue pharmacokinetics. 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 cefuroxime in microdialysis samples consisted of a reversed phase C18 column, flow rate of 1 ml/min and a detection wavelength of 280 nm. Mobile phase used for microdialysis and plasma samples consisted of methanol: 0.1M phosphate buffer (pH 5) (1:3). The retention time was 4.28 min. The calibration curves for microdialysis samples were linear in the range of 100-14,000 ng/ml with a correlation coefficient larger than 0.99. The lower limit of quantification (LLOQ) was 100 ng/ml for microdialysis samples.;The kinetics of cefuroxime was investigated in 3 female pathogen-free New Zealand albino rabbits. Two microdialysis probes were implanted into the skin of a tranquilized rabbit and perfused with lactated ringer's solution. Cefuroxime was administered by means of iontophoresis in a randomized cross-over experimental design in. Microdialysis samples were collected at selected time intervals. Retrodialysis was performed on each probe at the start of each experiment to assess probe recovery and correct the dialysate concentration to reflect the actual interstitial fluid concentration.;The results of these studies show that by means of one hour iontophoresis, cefuroxime concentration in skin reaches MIC in approximately 20 minutes. The concentration achieves the maximum at approximately 45 minutes, after that it declines gradually. In summary, MIC is maintained for 70 minutes.