Concentration‐Time profiles of Glyburide in Rats: Predictions using a Continuous Absorption Model

Most drugs are administered orally due to cost‐efficacy and increased patient compliance. However, the absorption of these drugs is subjected to complex biological processes and depends on the drug’s physicochemical properties. Prior to human trials, preclinical species such as rodents are utilized to evaluate efficacy and safety in vivo . Because animal studies are expensive and time‐consuming, it is beneficial to predict a drug’s pharmacokinetic profiles prior to in vivo studies. Pharmacokinetic modeling and simulation is useful for such predictions. The small intestine and colon of male Sprague Dawley rats were divided into 10 unequal segments to measure the change in luminal pH. Luminal contents were collected and directly measured under fed (n=4) and 12‐hour fasted (n=4) conditions. Glyburide is an oral anti‐diabetic medication that stimulates insulin secretion by blocking ATP‐dependent potassium channels in pancreatic beta cells. In vivo pharmacokinetic studies were performed to determine the effect of food. Fasted (n=4) and fed (n=4) male Sprague Dawley rats were dosed 5mg/kg of glyburide by oral gavage. Rats (n=2) were dosed intravenously to collect pharmacokinetic parameters. Blood samples were collected at 0.1, 0.25, 0.5, 1, 2, 4, 6, 10, and 24 hours post dose. Data were analyzed with non‐compartmental analysis. A continuous rodent absorption model was developed to predict the concentration‐time profiles of compounds based on rodent anatomical data collected in‐house and from the literature. Several physiological parameters were incorporated in the model, including small intestinal transit time, luminal pH, and transporter expression along the intestines. Rats fasted for 12 hours had a higher pH along the intestine that increased slowly, compared to fed rats. While the pH of the colon was higher in fasted rats, the cecum was not altered by fasted conditions. Fasted rats had an average glyburide AUC (0–24) of 2.7 μg*h/ml, while fed rats had an AUC (0–24) of 0.97 μg*h/ml. The mean apparent clearance (CL/F) was 1.8 L/min/kg for fasted rats and 5.1 L/min/kg for fed rats. The mean half‐life increased slightly from 10.6 hours in fasted rats to 11.6 hours in fed rats. Current predictions using the rodent continuous absorption model do not accurately describe the exposure profile of glyburide. To refine the model, further anatomical data collection and incorporation of fasted versus fed conditions are underway. Support or Funding Information This work was supported by NIH grants R01GM114369 and R01GM104178 to Swati Nagar and Ken Korzekwa.