Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios.

Article Details

Citation

Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC, Peterkin V, Koup JR, Ball SE

Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios.

Drug Metab Dispos. 2004 Nov;32(11):1201-8. doi: 10.1124/dmd.104.000794. Epub 2004 Aug 10.

PubMed ID
15304429 [ View in PubMed
]
Abstract

Glucuronidation is a listed clearance mechanism for 1 in 10 of the top 200 prescribed drugs. The objective of this article is to encourage those studying ligand interactions with UDP-glucuronosyltransferases (UGTs) to adequately consider the potential consequences of in vitro UGT inhibition in humans. Spurred on by interest in developing potent and selective inhibitors for improved confidence around UGT reaction phenotyping, and the increased availability of recombinant forms of human UGTs, several recent studies have reported in vitro inhibition of UGT enzymes. In some cases, the observed potency of UGT inhibitors in vitro has been interpreted as having potential relevance in humans via pharmacokinetic drug-drug interactions. Although there are reported examples of clinically relevant drug-drug interactions for UGT substrates, exposure increases of the aglycone are rarely greater than 100% in the presence of an inhibitor relative to its absence (i.e., AUCi/AUC < or = 2). This small magnitude in change is in contrast to drugs primarily cleared by cytochrome P450 enzymes, where exposures have been reported to increase as much as 35-fold on coadministration with an inhibitor (e.g., ketoconazole inhibition of CYP3A4-catalyzed terfenadine metabolism). In this article the evidence for purported clinical relevance of potent in vitro inhibition of UGT enzymes will be assessed, taking the following into account: in vitro data on the enzymology of glucuronide formation from aglycone, pharmacokinetic principles based on empirical data for inhibition of metabolism, and clinical data on the pharmacokinetic drug-drug interactions of drugs primarily cleared by glucuronidation.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
AlvocidibUDP-glucuronosyltransferase 1-1ProteinHumans
No
Substrate
Details
CarvedilolUDP-glucuronosyltransferase 1-1ProteinHumans
No
Substrate
Details
CarvedilolUDP-glucuronosyltransferase 2B4ProteinHumans
Unknown
Substrate
Details
CarvedilolUDP-glucuronosyltransferase 2B7ProteinHumans
Unknown
Substrate
Details
CodeineCytochrome P450 3A4ProteinHumans
Unknown
Substrate
Details
EthinylestradiolUDP-glucuronosyltransferase 1-1ProteinHumans
No
Substrate
Inducer
Details
FenofibrateUDP-glucuronosyltransferase 1-9ProteinHumans
No
Substrate
Details
FurosemideUDP-glucuronosyltransferase 1-1ProteinHumans
No
Substrate
Details
GemfibrozilUDP-glucuronosyltransferase 1-1ProteinHumans
No
Substrate
Inhibitor
Details
GlipizideUDP-glucuronosyltransferase 1-1ProteinHumans
No
Substrate
Details
LamotrigineUDP-glucuronosyltransferases (UGTs) (Protein Group)Protein groupHumans
Unknown
Substrate
Details
LevothyroxineUDP-glucuronosyltransferase 1-1ProteinHumans
No
Substrate
Details
MetronidazoleUDP-glucuronosyltransferase 1-1ProteinHumans
No
Substrate
Details
NaloxoneUDP-glucuronosyltransferase 1-1ProteinHumans
No
Substrate
Details
PropofolUDP-glucuronosyltransferase 1-1ProteinHumans
Unknown
Substrate
Inhibitor
Details
RaloxifeneUDP-glucuronosyltransferase 1-1ProteinHumans
No
Substrate
Details
SilibininUDP-glucuronosyltransferase 1-1ProteinHumans
No
Inhibitor
Details
Sodium aurothiomalateUDP-glucuronosyltransferase 1-1ProteinHumans
No
Inhibitor
Details
TramadolUDP-glucuronosyltransferase 1-1ProteinHumans
No
Substrate
Details
ZidovudineUDP-glucuronosyltransferase 1-1ProteinHumans
No
Substrate
Inducer
Details
Drug Interactions
DrugsInteraction
Abacavir
Nelfinavir
The metabolism of Abacavir can be increased when combined with Nelfinavir.
Abacavir
Phenytoin
The metabolism of Abacavir can be increased when combined with Phenytoin.
Abacavir
Desogestrel
The metabolism of Abacavir can be increased when combined with Desogestrel.
Abacavir
Lamotrigine
The metabolism of Abacavir can be increased when combined with Lamotrigine.
Abacavir
Efavirenz
The metabolism of Abacavir can be increased when combined with Efavirenz.
Abacavir
Primidone
The metabolism of Abacavir can be increased when combined with Primidone.
Abacavir
Tipranavir
The metabolism of Abacavir can be increased when combined with Tipranavir.
Abacavir
Ethinylestradiol
The metabolism of Abacavir can be increased when combined with Ethinylestradiol.
Abacavir
Rifampicin
The metabolism of Abacavir can be increased when combined with Rifampicin.
Abacavir
Phenobarbital
The metabolism of Abacavir can be increased when combined with Phenobarbital.
Interactions
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