A Mathematical Description of the Functionality of Correction Factors Used in Allometry for Predicting Human Drug Clearance DMD#4135 2 Running title: Functionality of correction factors used in allometry

Abstract The functionality of the correction factors, maximum life-span potential (MLP) and brain weight (BrW) used in allometry, is mathematically described. Correction by MLP or BrW is equivalent to a multiplication of some constants by the predicted values in humans from simple allometry, but they have no relationship to measured pharmacokinetic parameters in the animal species. The values of these constants (F MLP or F BrW ) were calculated for some commonly used combinations of animal species. For all combinations of animal species, the value of F BrW is always greater than F MLP with a fold-increase of about 1.3 to 1.9. Different combinations of species give different values of F BrW and F MLP . In addition, the role of correction factors (MLP and BrW) or the "rule of exponents" (ROE) was evaluated. An intrinsic defect in using correction factors or ROE was revealed; different study designs will produce significantly different prediction results. However, ROE may still serve as a useful practical approach in predicting human CL since it was derived from real observations and has been applied to many examples

Dose Tolerance and Pharmacokinetic Studies of L (+) Pseudoephedrine Capsules in Man

Dose tolerance and pharmacokinetic studies of pseudoephedrine sustained action capsules were performed in thirty-three adult male subjects who received either 120 mg or 150 mg capsules every twelve hours for seven consecutive days in a double-blind parallel design study. Although only one subject in the 150 mg group was discontinued prematurely from this study, a large number of side effects typical of CNS stimulation were seen. A placebo effect might account for a portion of these complaints, however symtoms evaluated as being due to drug were significantly more severe and persistent in the 150 mg group. Pulse rates showed a persistent and significant increase while systolic and diastolic blood pressure fell from the baseline values in both groups. A pharmacokinetic analysis of the pseudoephedrine plasma concentration-time data provided estimates of half-life and the volume of distribution/availability ratio. The values obtained were in good agreement with values reported by others. Half-life was not influenced by urine pH probably as a result of the narrow range of urine pHs observed in the subjects. Calculations of relative bioavailability suggest that the 120 mg capsule formulation has a 30% greater bioavailability compared to the 150 mg capsule

A population pharmacokinetic model for creatinine with and without ingestion of a cooked meat meal

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