3.1.8.3 Inhibition of Glucuronide Renal Clearance Glucuronides are cleared
by either biliary or renal clearance. Biliary secretion of glucuronides is largely
mediated by MRP2 (ABCC2) whereas renal clearance is due to a combination
of glomerular filtration and active secretion. Probenecid, an anion transport
inhibitor, is known to inhibit the secretion of glucuronides and can result in
high concentrations of circulating glucuronides. In some cases, especially acyl
glucuronides, plasma esterases or tissue beta-glucuronidase can cleave the
glucuronide back to parent resulting in reduced apparent clearance and
elevated parent drug concentrations. This reversible metabolism is also
observed in renal impairment and is sometimes termed as a ‘‘futile cycle’’ of
metabolism. Similar drug interactions would be expected with inhibitors of
MRP2 in terms of reduced biliary secretion of glucuronides in the liver.
3.1.8.4 Inhibition of P450-Mediated Metabolism by Glucuronide
Metabolites Recently, Ogilvie et al (2006) reported that the glucuronide of
gemfibrozil was a potent CYP2C8 inhibitor. The interaction of gemfibrozil
with cerivastatin resulted in multiple cases of severe rhabdomyolysis and
several deaths resulting in the withdrawal of cerivastatin from the US market.
Gemfibrozil itself is a weak CYP2C8 inhibitor and also inhibits the
glucuronidation of statins, a necessary step in the formation of the lactone
metabolites. Cerivistatin is glucuronidated and oxidatively metabolized by
CYP2C8 and CYP3A4. The finding that the gemfibrozil glucuronide was an
even more potent inhibitor of CYP2C8 than gemfibrozil, coupled with the high
local hepatic concentrations in the liver, suggest that glucuronidation had a
major role in the observed interaction.
3.1.9 Summary
Glucuronidation is a critical Phase II conjugation reaction for many endogenous
and exogenous compounds. The UGT enzyme superfamily catalyzes this
reaction. UGT substrates, inducers and inhibitors, and analytical techniques to
measure glucuronidation are discussed. Drug glucuronidation is an important
contributor to drug–drug interactions via various mechanisms. The pharmaco-
genomic knowledge concerning these enzymes is rapidly maturing and clearance
of some important anticancer and HIV drugs is affected by polymorphisms. In an
effort to reduce the contribution of P450 enzymes in the elimination of drug
candidates to avoid interactions, one must be aware of potential problems that
can arise by interactions in this important conjugation pathway.
3.2 Cytosolic Sulfotransferases
Sulfonation is a common ‘‘Phase II’’ conjugation reaction that occurs across
species. Numerous endobiotics as well as xenobiotics are sulfonated in the
human body. This process of sulfonation was discovered by Baumann with the
62 CONJUGATIVE METABOLISM OF DRUGS