3.1.8.1 Common Drug Metabolizing Enzyme Lamotrigine (LTG) is a
diaminotriazine antiepileptic drug that is widely used and promoted due to
its lack of interaction with other AEDs that are oxidatively metabolized by
P450s. Greater than 90% of LTG is excreted asN-glucuronide metabolites.
However, LTG is subject to inductive interactions with carbamazepine,
phenytoin, and phenobarbital that reduce the half-life from 24 h to
approximately 12 h necessitating dose adjustment. In contrast, patients who
are taking valproate have a half-life of 60–80 h due to inhibition of LTG
metabolism. LTG is a UGT1A4 substrate and recently Miners and coworkers
suggested thatN-glucuronidation may also be catalyzed UGT2B7 based on
inhibition with valproic acid. Valproic acid is given at high doses and is a
substrate for multiple UGT enzymes including UGT1A3–1A10, and 2B7
(Argikar, 2005; Staines, 2004). In a transgenic mouse expressing the human
UGT1A complex, we have found induction of lamotrigine glucuronidation
with pregnenolone-16a-carbonitrile (a mouse PXR activator) and TCDD (an
Ah receptor ligand) (Chen, 2005).UGT1A4is a pseudogene in mice producing
an inactive protein. In humans, rifampin increases LTG clearance (Ebert,
2000), suggesting that PXR activators will increase UGT1A4 expression.
Zidovudine (AZT) is an HIV reverse transcriptase inhibitor and chain
terminator that is extensively glucuronidated (70% of the dose) primarily by
UGT2B7. Metabolism of AZT is induced by rifampin (PXR), ritonavir,
tipranavir, and efavirenz. Zidovudine clearance is inhibited by methadone
(McCance-Katz, 1998) (opiates like codeine and morphine are UGT2B7
substrates), fluconazole Trapnell, 1998, atovaquone (Lee, 1996), and valproate
(Lertora, 1994). Rifampin increased the formation clearance to AZT-
glucuronide by twofold (Gallicano, 1999).
3.1.8.2 Metabolic Switching Inhibition of glucuronidation may result in
drug toxicity by directly increasing parent compound concentrations or can
lead to metabolic switching to oxidative pathways that produce reactive
metabolites. In acetaminophen acute hepatotoxicity, glucuronidation, and
sulfation pathways are saturated resulting in more of the drug metabolized to
NAPQI, the reactive quinone imine metabolite. Once glutathione is depleted,
NAPQI reacts with cellular macromolecules leading to cell death. In our
laboratory, we have studied the bioactivation of naltrexone and interactions
with NSAIDs. In the course of an open label trial of patients taking naltrexone
for pathologic gambling and who were also exposed to NSAIDs, a high
percentage of patients had elevated liver enzymes. Subsequent studies have
demonstrated that some NSAIDs, specially fenamate derivatives, are potent
UGT2B7 inhibitors, the enzyme responsible for naltrexone glucuronidation.
Naltrexone was metabolized by CYP3A4 in the presence of glutathione to two
glutathione conjugates presumably through a catechol/quinone intermediate
(Kalyanaraman, MS thesis, 2005). Thus, inhibition of glucuronidation leading
to greater production of the catechol metabolite may be responsible for this
interaction observed in the clinical studies.
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