This article is available online at http://dmd.aspetjournals.org ABSTRACT:A metabolite formed by incubation of human liver microsomes, etoposide, and UDP-glucuronic acid was identified as etoposide glucuronide by liquid chromatography-tandem mass spectrometry analysis. According to the derivatization with trimethylsilylimidazole (Tri-Sil-Z), it was confirmed that the glucuronic acid is linked to an alcoholic hydroxyl group of etoposide and not to a phenolic group. Among nine recombinant human UGT isoforms (UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A8, UGT1A9. UGT1A10, UGT2B7, and UGT2B15), only UGT1A1 exhibited the catalytic activity of Etoposide [4Ј-demethylepipodophyllotoxin-9-(4,6-O-ethylidene)-␤-D-glucopyranoside] is one of the clinically important antitumor agents derived from 4Ј-demethylepipodophyllotoxin, which is an extract from the plants Podophyllum peltatum and Podophyllum emodi (Clark and Slevin, 1987;Stähelin and von Wartburg, 1991). It is widely used in the treatment of testicular cancer, small cell lung cancer, and certain lymphomas (O'Dwyer et al., 1985). Etoposide causes tumor cell killing through DNA strand breakage resulting from the interaction of etoposide with the enzyme topoisomerase II and DNA (Ross et al., 1984).In humans, the disposition of etoposide is described as a biphasic process with a distribution half-life of about 1.5 h and terminal elimination half-life ranging from 4 to 11 h (PDR, 2000). Clearance of etoposide occurs by direct renal excretion and metabolism. Roughly 35% of the administered drug is excreted into urine as a parent drug (Hande et al., 1984;Sinkule et al., 1984), but less than 3% is excreted into bile (Joel et al., 1996). Several metabolites were identified in human plasma and urine such as hydroxy acid derivatives, cis-(picro) lactone, 3Ј-demethyletoposide, and etoposide glucuronide (Clark and Slevin, 1987;Stewart, 1994). It has been reported that 58 and 19% of the administered drug is excreted as hydroxy acid into urine and bile, respectively (Clark and Slevin, 1987); less than 5 and 1% of the administered drug is found as cis-(picro) lactone in plasma and urine, respectively (Holthuis et al., 1986). It has been reported that 3Ј-demethylation of etoposide, a minor metabolite, is catalyzed by CYP3A4 (Relling et al., 1994). Etoposide glucuronide accounts for the disposition of 15 to 35% of administered etoposide (D'Incalci et al., 1986;Hande et al., 1988).Glucuronidation is catalyzed by UDP-glucuronosyltransferase (UGT 1 ) enzymes (Miners and Mackenzie, 1991). It is well known that there are many isoforms of mammalian UGT enzymes (Tukey and Strassburg, 2000). UGT1 and UGT2 have been shown to catalyze the glucuronidation of xenobiotics. The UGT1 and UGT2 genes seem to be structurally different in that UGT1 proteins result from alternate splicing of different first exons with five shared exons encoded by the UGT1 gene complex, whereas UGT2 proteins seem to be encoded by unique genes. In the human genome, at least 13 different first exons have been identified for the UGT1...

1. The absorption, metabolism and excretion of teneligliptin were investigated in healthy male subjects after a single oral dose of 20 mg [(14)C]teneligliptin. 2. Total plasma radioactivity reached the peak concentration at 1.33 h after administration and thereafter disappeared in a biphasic manner. By 216 h after administration, ≥90% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 45.4% and 46.5%, respectively. 3. The most abundant metabolite in plasma was a thiazolidine-1-oxide derivative (designated as M1), which accounted for 14.7% of the plasma AUC (area under the plasma concentration versus time curve) of the total radioactivity. The major components excreted in urine were teneligliptin and M1, accounting for 14.8% and 17.7% of the dose, respectively, by 120 h, whereas in faeces, teneligliptin was the major component (26.1% of the dose), followed by M1 (4.0%). 4. CYP3A4 and FMO3 are the major enzymes responsible for the metabolism of teneligliptin in humans. 5. This study indicates the involvement of renal excretion and multiple metabolic pathways in the elimination of teneligliptin from the human body. Teneligliptin is unlikely to cause conspicuous drug interactions or changes in its pharmacokinetics patients with renal or hepatic impairment, due to a balance in the elimination pathways.

Drug-drug interactions (DDIs) caused by the inhibition of hepatic uptake transporters such as organic anion transporting polypeptide (OATP) can affect therapeutic efficacy and cause adverse reactions. We investigated the potential utility of pitavastatin as an in vivo probe substrate for preclinically studying OATP-mediated DDIs using cynomolgus monkeys. Cyclosporine A (CsA) and rifampicin (RIF), typical OATP inhibitors, inhibited active uptake of pitavastatin into monkey hepatocytes with half-maximal inhibitory concentration values comparable with those in human hepatocytes. CsA and RIF increased the area under the plasma concentration-time curve (AUC) of intravenously administered pitavastatin in cynomolgus monkeys by 3.2-and 3.6-fold, respectively. In addition, there was no apparent prolongation of the elimination half-life of pitavastatin due to the decrease in both hepatic clearance and volume of distribution. These findings suggest that DDIs were caused by the inhibition of hepatic uptake of pitavastatin. CsA and RIF increased the AUC of orally administered pitavastatin by 10.6-and 14.8-fold, respectively, which was additionally caused by the effect of the CsA and RIF in the gastrointestinal tract. Hepatic contribution to the overall DDI for oral pitavastatin with CsA was calculated from the changes in hepatic availability and clearance, and it was shown that the magnitude of hepatic DDI was comparable between the present study and the clinical study. In conclusion, pharmacokinetic studies using pitavastatin as a probe in combination with drug candidates in cynomolgus monkeys are useful to support the assessment of potential clinical DDIs involving hepatic uptake transporters.

ABSTRACT:A method for the direct determination of imipramine N-glucuronidation in human liver microsomes by high-performance liquid chromatography with UV detection was developed. Imipramine was incubated with human liver microsomes and UDP-glucuronic acid. The Eadie-Hofstee plots of imipramine N-glucuronidation in human liver microsomes were biphasic. For the high-affinity component, the