Abstract
To obtain more insight in the relationship between physicochemical properties of cationic drugs and their hepatobiliary transport rate, a series of 12 aminosteroidal neuromuscular blocking agents (NMBAs), supplemented with data of four related NMBAs from the literature, were investigated in the isolated perfused rat liver. A significant correlation was found between plasma protein binding and the partition coefficient octanol/Krebs (log P), confirming results from the literature with other organic cations. Evidence was found for a saturable hepatic uptake of several NMBAs, indicating that carrier-mediated uptake processes are involved. Hepatic uptake rate was closely related to the lipophilicity of the compounds; the initial extraction ratio, the apparent clearance and the intrinsic clearance were significantly correlated to log P. We did not find a significant correlation between biliary clearance and lipophilicity in the current series of compounds. Pharmacokinetics analysis of perfusate disappearance and biliary excretion data revealed that a considerable fraction of the dose of these bulky organic cations is stored in the liver and seems to not be directly available for biliary excretion. This finding is in line with earlier observations showing a pronounced accumulation of this type of compounds in mitochondria and lysosomes.
Footnotes
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Send reprint requests to: Dr. J. H. Proost, University Centre for Pharmacy, Department of Pharmacokinetics and Drug Delivery, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
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↵1 This work was supported by Organon Teknika (Turnhout, Belgium).
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↵2 Present address: Groningen Institute for Drug Studies (GIDS), University Centre for Pharmacy, Department of Pharmacokinetics and Drug Delivery, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
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↵3 Present address: Research Group for Experimental Anesthesiology and Clinical Pharmacology, University Hospital, Department of Anesthesiology, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
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↵4 GIDS is part of the research school Groningen Utrecht Institute for Drug Exploration (GUIDE).
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↵5 J. H. Proost, Groningen Institute for Drug Studies, unpublished observations.
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↵7 Lanting, A. B. L., Ensing, K., Drenth, B. F. H., Meijer, D. K. F. and De Zeeuw, R. A.: Stereochemical factors in the hepatic transport and metabolism of the organic cations N-methyl dextrorphan and N-methyl levorphanol in the isolated perfused rat liver, submitted manuscript.
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↵8 J. H. Proost, Groningen Institute for Drug Studies, unpublished observations.
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↵9 H. Koepsell and P. J. Meijer, personal communication.
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↵6 D. K. F. Meijer, Groningen Institute for Drug Studies, unpublished observations.
- Abbreviations:
- NMBA
- neuromuscular blocking agent
- P
- partition coefficient
- OCT1
- organic cation transporter 1
- OATP
- organic anion transporting polypeptide
- MRP
- multidrug resistance-related protein
- HPLC
- high-performance liquid chromatography
- DAS
- 9,10-dimethoxyanthracene-2-sulfonate
- Received November 15, 1996.
- Accepted March 17, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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