ISSN:
1573-8744
Keywords:
carrier-mediated system
;
flow-limited system
;
diffusion-limited system
;
influx
;
efflux
;
excretion
;
bromosulfophthalein glutathione conjugate (BSP-GSH)
;
extraction ratio
;
unbound logarithmic average concentration
;
unbound tissue concentration
;
apparent distribution equilibrium ratio
;
tissue-to-plasma partition coefficient
Source:
Springer Online Journal Archives 1860-2000
Topics:
Chemistry and Pharmacology
Notes:
Abstract Concentration-dependent changes in the hepatic extraction ratio E and tissue accumulation of drugs were examined in a simulation study, wherein plasma protein binding, flow, and mode of entry were altered. A tubular flow model that described carrier-mediated (influx:K ml =20 μM,V max1=1000 nmol min−1;effux,K m2=200 μM,V max2=250 nmol min−1), flow-limited (influx clearanceCL in=efflux clearanceCL ef=50 ml min−1), or diffusion-limited (CL in=CL ef=0.1 ml min−1) hepatocytic entry was employed; drug removal was solelyvia biliary excretion (K m3=100 μM,V max3=1500 nmol min−1). Other parameter space and the combination of carriermediated transport and passive diffusion were also explored. Increased plasma protein binding reduced the hepatic extraction of the substrate, and in some instances, constituted the ratecontrolling factor, especially at lower input concentrations for which tighter binding existed. Increased flow rate also brought about a reduction inE, affectingE almost inversely when values ofE were low (e.g., for the diffusion-limited case or at higher input concentration). Tissue accumulation patterns and the apparent tissue distribution equilibrium ratio, i.e., tissue to plasma unbound concentration ratioK p, differed among the systems. The behavior ofK p may be used as an identifier for the mode of drug transport: A declining (concave-down)K p curve or a parabolicK p that approached unity with input concentration (C In) is associated with carrier-mediated entry; a risingK p curve that approaches unity withC In suggests flow limitation; and a waning concaveupK p curve of very low magnitude represents diffusion limitation. Since the unbound tissue concentration (C t) differs from the logarithmic average of the unbound input and output concentrations in plasma ( $$\hat C_u$$ ) for carrier-mediated and diffusion-limited systems, excretion parameters may be obtained only upon fitting of the overall excretion ratevs.C t in the Michaelis-Menten equation; whereas when data are fitted with $$\hat C_u$$ , the rate-limiting step, influx, or deviations of influx, efflux, and excretion, will be obtained. WhenC t equals $$\hat C_u$$ , as in flow-limited systems, accurate excretion parameters will be provided with the fitting of data against eitherC t or $$\hat C_u$$ .
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF02353638
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