MODEL INDEPENDENT ANALYSIS OF SELECTED PHARMACOKINETIC PROCESSES, THEORY AND APPLICATION (NEPHRECTOMY, CEREBROSPINAL, REGRESSION)

MICHAEL DAVIS KAROL, Purdue University

Abstract

The effects of nephrectomy on the pharmacokinetics of theophylline are examined. Both model dependent and model independent approaches were applied. No individual parameter of the model independent function showed a significant change following nephrectomy. Two model dependent approaches were taken. The first was to determine if the difference in data could be accounted for by a change in the first-order central compartment elimination rate constant. The second was to determine if the first-order distribution constants could account for the change. Results indicated that either elimination or distribution constants could account for the difference and that the model dependent approach did not yield a unique explanation. The transport of theophylline into and out of the cerebrospinal fluid was also investigated. Two model independent schemes describing theophylline transfer were compared. The first model assumes that the rate of transfer is proportional to the difference in free drug concentration in the serum and cerebrospinal fluid (CSF) whereas the second model has the added feature that drug may also be transferred from the CSF to the blood by the continuous secretion of CSF into the blood. The results indicated that the "diffusion and flow" model best describes the transfer process. The effect of alteration of bulk flow of cerebrospinal fluid on the CSF elimination of nicotine and indocyanine green was investigated. Bulk flow rate was altered by the administration of acetazolamide. The results of model independent analysis indicated that the introduction of acetazolamide into the general circulation increases the rate of removal of nicotine from the CSF. Elevated pressure associated with acetazolamide suggests pressure as a possible mechanistic factor.

Degree

Ph.D.

Subject Area

Pharmaceuticals

COinS