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Allosteric Enzyme- and Transporter-Based Interactions

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Book cover Enzyme- and Transporter-Based Drug-Drug Interactions

Abstract

Allosterism in enzymes and transporters can result in alterations in kinetic profiles and in rates of metabolism and transport. Cooperativity due to allosteric interactions has been observed with drug-metabolizing enzymes such as the cytochromes P450 and the uridine glucuronosyltransferases. In addition, transporters such as P-glycoprotein and breast cancer resistance protein have been demonstrated to also exhibit allosteric interactions resulting in cooperativity. Kinetic profiles such as autoactivation (sigmoidal profile), biphasic and substrate inhibition have been observed to occur due to homotropic cooperativity, and heteroactivation has been observed to occur due to heterocooperativity. Numerous examples of all types of allosteric interactions have been observed in vitro but in vivo examples are limited. The correct kinetic equation should be applied to kinetic profiles to properly estimate kinetic parameters for use in in vitro–in vivo correlations.

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Abbreviations

P450 s:

Cytochrome P450 s

UGT s:

UDP-glucuronosyltransferases

SULT s:

sulfotransferases

P-gp:

P-glycoprotein

CBZ:

carbamazepine

CBZ-E:

carbamazepine–epoxide

DHEA:

dehydroepiandrosterone

UDPGA:

uridine diphosphate glucuronic acid

PhIP:

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

MDCK-MDR:

Madin Darby canine kidney-multiple drug resistance

BCRP:

breast cancer resistance protein

HLMs:

human liver microsomes

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Authors and Affiliations

  1. Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA

    Murali Subramanian

  2. Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA

    Timothy S. Tracy

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  1. Murali Subramanian
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  2. Timothy S. Tracy
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Correspondence to Timothy S. Tracy .

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Editors and Affiliations

  1. Leslie Dan Fac. Pharmacy, University of Toronto, College Street 144, Toronto, M5S 3M2, Canada

    K. Sandy Pang

  2. Bristol-Myers Squibb Company, Princeton, 08543, U.S.A.

    A. David Rodrigues

  3. AstraZeneca UK, Alderley Park, Macclesfield, Cheshire, SK10 4TF, United Kingdom

    Raimund M. Peter

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Subramanian, M., Tracy, T.S. (2010). Allosteric Enzyme- and Transporter-Based Interactions. In: Pang , K., Rodrigues, A., Peter, R. (eds) Enzyme- and Transporter-Based Drug-Drug Interactions. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0840-7_20

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