The Pharmacokinetics and Pharmacodynamics of CNS-Acting Agents.

The first part of my research project investigated how pharmacokinetic/ pharmacodynamic modeling of ordered categorical and continuous Visual Analog scales (VAS) may provide insight into drug response by utilizing small samples of subjects. Two lorazepam adverse events (AEs), sleepiness and dizziness, were modeled to identify differences in pharmacodynamic parameters and differences compared to relative incidence rates in the drug label. Healthy volunteers (n=20) received single oral doses of 2 mg lorazepam or placebo in a randomized, double-blind, cross-over fashion. A 7 point categorical scale and the VAS, which measure the intensity of AEs, were serially administered over 24 hr. The maximum score (MaxS) and area under the effect curve (AUEC) were determined by noncompartmental methods and compared using a paired t-test. Individual categorical scores were modeled in NONMEM using a logistic function while VAS scores were logistically transformed to normalize right-skewed VAS scores and modeled in NONMEM. AUEC and MaxS for sleepiness were significantly higher than dizziness. Model slope estimates were similar for sleepiness and dizziness, but baseline logits were significantly higher for sleepiness. Therefore, the higher intensity of sleepiness may be directly related to baseline differences (no drug present) while the increase in intensity due to drug was relatively similar for both AEs. The second part of my research project investigated the in vivo relevance of the PEPT2 transporter on systemic exposure, tissue distribution, and renal handling of the endogenous dipeptide carnosine after a 1 nmol/g intravenous dose in wild-type and Pept2 null mice. PEPT2 ablation resulted in a 2 -fold increase in systemic clearance of carnosine resulting in a decreased systemic exposure of dipeptide. Carnosine uptake was substantially reduced in the kidney and renal clearance increased 17-fold due to decreased fractional reabsorption of carnosine. This finding reflected the ability of PEPT2 to mediate 83% of carnosine’s total reabsorption in tubular fluid. The cerebrospinal fluid to plasma concentration ratios for carnosine were 8-fold greater in Pept2-deficient versus Pept2-competent mice. The results demonstrate that PEPT2 is the predominant peptide transporter in the physiological handling of carnosine in kidney, and that it significantly limits carnosine exposure in cerebrospinal fluid.Ph.D.Pharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/61735/1/makamal_1.pd