Role for protein kinase C delta in the functional activity of human UGT1A6: implications for drug-drug interactions between PKC inhibitors and UGT1A6.

Many UDP-glucuronosyltransferases (UGTs) require phosphorylation by protein kinase C (PKC) for glucuronidation activity. Inhibition of UGT phosphorylation by PKC inhibitor drugs may represent a novel mechanism for drug-drug interactions. The potential for PKC-mediated inhibition of human UGT1A6, an isoform involved in the glucuronidation of drugs such as acetaminophen (paracetamol) and endogenous substrates including serotonin, was evaluated using various cell model systems. Of ten different PKC inhibitors screened for their effects on acetaminophen glucuronidation by human LS180 colon cells, only rottlerin (PKC delta selective inhibitor; IC(50) = 9.0 +/- 1.2 microM) and the non-selective PKC inhibitors (calphostin-C, curcumin and hypericin) decreased glucuronidation by more than 50%. Using UGT1A6-infected Sf9 insect cells, calphostin-C and hypericin showed three times more potent inhibition of serotonin glucuronidation in treated whole cells versus cell lysates. However, both curcumin and rottlerin showed significant direct inhibition and so (indirect) PKC effects could not be differentiated in this model system. Of nine PKC isoforms co-expressed with UGT1A6 in human embryonic kidney 293T cells only PKC delta increased protein-normalized UGT1A6-mediated serotonin glucuronidation significantly (by 63% +/- 4%). These results identify an important role for PKC delta in UGT1A6-mediated glucuronidation and suggest that PKC delta inhibitors could interfere with glucuronidation of UGT1A6 substrates.

Short-term clarithromycin administration impairs clearance and enhances pharmacodynamic effects of trazodone but not of zolpidem.

The kinetic and dynamic interactions of 5 mg zolpidem and 50 mg trazodone with 500 mg clarithromycin (4 doses given over 32 h) were investigated in a 5-way double crossover study with 10 healthy volunteers. The five treatment conditions were: placebo + placebo; zolpidem + placebo; zolpidem + clarithromycin; trazodone + placebo; and trazodone + clarithromycin. Coadministration of clarithromycin increased trazodone area under the curve, prolonged elimination half-life, increased peak plasma concentration (C(max)), and reduced oral clearance. In contrast, clarithromycin had no significant effect on any kinetic parameter for zolpidem. Clarithromycin did not potentiate sedation caused by zolpidem. However, clarithromycin coadministered with trazodone significantly increased self- and observer-rated sedation and ratings of feeling "spacey." Thus, short-term clarithromycin coadministration significantly impairs trazodone clearance, elevates plasma concentrations, and enhances sedative effects. However, clarithromycin has no significant kinetic or dynamic interaction with zolpidem.