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OtherDRUG METABOLISM AND DISPOSITION

Carrier-Mediated Active Transport of the Glucuronide and Sulfate of 6-Hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) into Rat Liver: Quantitative Comparison of Permeability in Isolated Hepatocytes, Perfused Liver and Liver in Vivo

Osamu Takenaka, Toru Horie, Hiroshi Suzuki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics February 1997, 280 (2) 948-958;
Osamu Takenaka
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Toru Horie
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Hiroshi Suzuki
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Yuichi Sugiyama
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Abstract

The hepatic uptake of glucuronic acid and sulfate conjugates of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040), a dual inhibitor of 5-lipoxygenase and thromboxane A2 synthetase, was investigated in rats. The biliary excretion clearance values for the glucuronide and the sulfate, obtained after i.v. administration of E3040, were similar and corresponded to approximately 30% of the hepatic blood flow rate. The influx clearance values of E3040 conjugates in the presence of 3% bovine serum albumin, measured by a multiple indicator dilution method in the perfused liver, were 1.20 ml/min/g liver for the glucuronide and 0.74 ml/min/g liver for the sulfate, which were twice and equal to the normal hepatic plasma flow rate, respectively, which suggests the presence of an efficient transport system(s). The uptake of E3040 conjugates into the isolated hepatocytes is mediated by Na+-independent active transport system(s), which is inhibited by dibromosulfophthalein and bile acids. The uptake for the sulfate had high-affinity and high-capacity transport activity (Km = 25 μM; V max = 7.8 nmol/min/106 cells) compared with that for the glucuronide (Km = 59 μM; V max = 2.2 nmol/min/106 cells). The uptakes of E3040 conjugates (glucuronide, sulfate) exhibited a mutual competitive inhibition. It is suggested that both conjugates share a multispecific organic anion transporter located on the sinusoidal membrane.

Footnotes

  • Send reprint requests to: Yuichi Sugiyama, Ph.D., Faculty of Pharmaceutical Sciences, The University of Tokyo, Hongo Bunkyo-ku, Tokyo 113, Japan.

  • Abbreviations:
    E3040
    6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole
    [14C]E3040
    [2-14C]6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole dihydrochloride
    SD rats
    Sprague-Dawley rats
    DBSP
    dibromosulfophthalein
    HEPES
    N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid
    MID method
    multiple indicator dilution method
    HPLC
    high-performance liquid chromatography
    BSA
    bovine serum albumin
    TLC
    thin-layer chromatography
    AUC∞
    the area under the plasma concentration-time profiles from zero to infinity
    CLbile
    the biliary excretion clearance
    CLrenal
    the urinary excretion clearance
    CLu,renal
    the unbound urinary excretion clearance
    Xbile
    the amount excreted into the bile
    Xurine
    the amount excreted into the urine
    CLtot
    the total body clearance
    PSinf
    the influx clearance
    PSu,inf
    the unbound influx clearance
    Kinf
    the influx rate constant
    Keff
    the efflux rate constant
    Kseq
    the sequestration rate constant
    Km
    Michaelis constant
    Vmax
    maximal uptake rate
    Pdif
    the nonspecific uptake clearance
    LUR
    the first-pass liver uptake ratio
    UWL
    the unstirred water layer
    PCMBS
    p-chloromercuriphenylsulfonic acid
    DIDS
    4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid
    FCCP
    carbonyl cyanide-p-(trifluoromethoxy)-phenylhydrazone
    C/M
    cell-to-medium concentration
    • Received May 24, 1996.
    • Accepted October 30, 1996.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 280, Issue 2
1 Feb 1997
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OtherDRUG METABOLISM AND DISPOSITION

Carrier-Mediated Active Transport of the Glucuronide and Sulfate of 6-Hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) into Rat Liver: Quantitative Comparison of Permeability in Isolated Hepatocytes, Perfused Liver and Liver in Vivo

Osamu Takenaka, Toru Horie, Hiroshi Suzuki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics February 1, 1997, 280 (2) 948-958;

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OtherDRUG METABOLISM AND DISPOSITION

Carrier-Mediated Active Transport of the Glucuronide and Sulfate of 6-Hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) into Rat Liver: Quantitative Comparison of Permeability in Isolated Hepatocytes, Perfused Liver and Liver in Vivo

Osamu Takenaka, Toru Horie, Hiroshi Suzuki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics February 1, 1997, 280 (2) 948-958;
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