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Effects of bladder resorption on pharmacokinetic data analysis

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Abstract

In modern pharmacokinetic analysis, the urinary bladder is usually viewed as a nonreturning compartment or storage site for renally excreted compounds. Our previous studies have indicated appreciable bladder resorption of drugs. The present study used computer simulations to evaluate the quantitative importance of several potential determinants of bladder resorption, namely the bladder resorption rate constant (k a), interval between bladder voiding (Δt void),ratio of renal elimination rate constant to overall elimination rate constant (k ex:k el ratio), andk el ort 1/2. The data identifiedk a, Δt void, andk ex:k el ratio as the three most important determinants of the rate and extent of bladder resorption. We further examined the errors introduced in the derived pharmacokinetic parameters due to omission of bladder resorption. Plasma concentration-time profiles and urinary excretion-time profiles were generated by simulations using different values ofk a, Δt void, andk ex:k el ratio. These profiles were used to derive the pharmacokinetic parameters, including the renal clearance (CL renal), total body clearance (CL total), nonrenal clearance (CL nonrenal),t 1/2, mean residence time (MRT), amount and fraction of dose excreted in urine (A ex andf e), and volume of distribution at steady state (Vd ss). Data show that resorption of drug from the bladder into the systemic circulation increased the area under the plama concentration-time profile,MRT andt 1/2, but decreasedCL renal,CL total,A ex, andf e.Vd ss was relatively unchanged. Overestimation of MRT andt 1/2 was dependent onk a,k ex:k el ratio,and Δt void. Underestimation inCL renal,A ex, andf e was not dependent on thek ex:k el ratio, but was affected by changes ink a and Δt void.CL renal andf e were the most sensitive pharmacokinetic parameters, with a≥50% underestimation at ak a value that we reported previously, for the bladder absorption of antipyrine in rats with intact urothelium. In summary, these data indicate (i) alteration in the plasma concentration-time profiles and urinary excretion-time profiles due to bladder resorption, and (ii) substantial over-or underestimation in the derived pharmacokinetic parameters due to erroneous omission of bladder resorption.

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Abbreviations

A ex :

Cumulative amount of drug excreted in urine

CL total :

Total body clearance

CL renal :

Renal clearance

CL nonrenal :

Nonrenal clearance

f c :

Fraction of unchanged drug excreted in urine

k a :

Bladder resorption rate constant

k ex :

Renal excretion rate constant

k nr :

Nonrenal elimination rate constant

k el :

Overall elimination rate constant

t 1/2 :

Half-life

Vd ss :

Volume of distribution at steady state

AUC :

Area under the plasma concentration-time profile

MRT :

Mean residence time

Δt void :

Time interval between urinary voids

AUMC :

Area under the (concentration x time) vs. time profile

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, The University of Tennessee, 874 Union Avenue, Room 5P Crowe Building, 38163, Memphis, Tennessee

    James T. Dalton

  2. Division of Urology and Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, 500 West 12th Avenue, 43210, Columbus, Ohio

    M. Guillaume Wientjes & Jessie L-S. Au

Authors
  1. James T. Dalton
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  2. M. Guillaume Wientjes
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  3. Jessie L-S. Au
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Additional information

Supported in part by MERIT grant R37 CA-49816, and Research Career Development Award K04 CA-01497 for J. L-S. Au, from The National Cancer Institute, National Institutes of Health, Department of Health and Human Services.

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Dalton, J.T., Wientjes, M.G. & Au, J.LS. Effects of bladder resorption on pharmacokinetic data analysis. Journal of Pharmacokinetics and Biopharmaceutics 22, 183–205 (1994). https://doi.org/10.1007/BF02353328

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