Pharmacokinetics of cimetidine in plasma and skin following IV-infusion administration in a rabbit model

Cimetidine (CMT) which is an H (2) receptor antagonist has been tested for several dermatological effects. However there is no conclusive work done that give evidence of CMT being a effective drug for skin disease. One of the reasons for variable result is that Cimetidine does not distribute to skin, therefore we decided to administer CMT systemically and see if CMT reaches to skin by measuring CMT concentration in dermis using microdialysis. There are several techniques by which we can monitor the concentration of drug in the tissue (skin) of animal or human such as biopsies, skin blister fluid sampling, imaging techniques, microdialysis (MD). We choose MD technique to monitor the concentration of CMT in the dermis (skin) over the other methods. The reason behind that was that MD is a semi invasive method, and allows sequential sampling over a long period of time which could lead to better results; also it gives the unbound drug concentration at the site of action which is the pharmacologically active.;To determine cimetidine in microdialysis and plasma samples a High Performance Liquid Chromatographic (HPLC) method was used. A reverse phase C18 column was used and mobile phase consist of Triethylamine: Acetonitrile: Phosphate Buffer (pH 6.81) in the ratio as follow {0.2:14:85.8}, flow rate of mobile phase was kept 1 ml/min and a UV detector was used with detection wavelength of 230 nm. The calibration curve for microdialysis and plasma were linear (R2 correlation coefficient was always grater than 0.99) for the range of 25--10000 ng/mL and 50--10000 ng/mL respectively.;Three female pathogen-free New Zealand albino rabbits were selected to study the kinetics of cimetidine in vivo. Each rabbit received short infra-venous (IV) infusions of three different doses 2.31, 4.62, 9.24 mg/kg of cimetidine according to a randomized cross-over design. Blood samples and microdialysis samples were collected at predetermined time intervals until 6 hours.;The plasma and skin concentration profiles were very different. Plasma concentration/time curves exhibited a dose-proportional pharmacokinetics and a multi-compartmental disposition while the skin concentration/time profiles were nonlinear with respect to dose and exhibited an unusual steady state concentration at the later times of the sampling. AUC and Cmax increased linearly with the dose for plasma while AUC and Cmax shows not linear behavior with increase in the dose and that the AUC increased disproportionally at the higher dose. These results points to a possible reason for the variable and controversial effects of cimetidine in skin diseases. Further study should be done to better understand this behavior.