The fate of a thiazolidinedione antidiabetic agent in rat and dog

Bolton, G C; Keogh, J. P.; East, Peter D.; Hollis, F. J.; Shore, A. D.

doi:10.3109/00498259609046738

Cited by 31 publications

(34 citation statements)

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“…Finally, troglitazone undergoes significant enterohepatic circulation and is excreted primarily through the liver (26,27). Rosiglitazone is renally excreted and does not undergo enterohepatic recirculation (28). These preclinical data suggested that rosiglitazone may have little or no potential to cause hepatotoxicity during clinical use.…”

Section: Diabetes Care 25:815-821 2002mentioning

confidence: 83%

Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials

2002

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OBJECTIVE -Troglitazone treatment has been associated with idiosyncratic hepatic reaction leading to hepatic failure and death in some patients. This raises questions regarding whether all thiazolidinediones or peroxisomal proliferator-activated receptor-␥ (PPAR-␥) agonists are hepatotoxic and whether data from clinical trials are adequate to detect a signal of potentially serious drug-related hepatotoxicity. The purpose of this study was to assess whether the idiosyncratic liver toxicity reported with troglitazone is molecule-specific or a thiazolidinedione class effect, based on liver enzyme data collected prospectively during phase 2/3 clinical trials with rosiglitazone, a new, potent, and specific member of the thiazolidinedione class. RESEARCH DESIGN AND METHODS-This is an analysis of liver function in type 2 diabetic patients at baseline and serially in 13 double-blind, 2 open-label active-controlled, and 7 open-label extension studies of rosiglitazone treatment conducted in outpatient centers throughout North America and Europe. The study comprised Ͼ6,000 patients aged 30 -80 years with type 2 diabetes. Patients underwent baseline liver function studies and were excluded from clinical trials if they had an alanine aminotransferase (ALT), aspartate aminotransferase (AST), or alkaline phosphatase value 2.5 times greater than the upper limit of the reference range. The main outcome measures were liver enzyme levels, which were assessed at screening, at baseline, and every 4 weeks for the first 3 months of treatment and at 6-to 12-week intervals thereafter. Patients with at least one on-therapy ALT value Ͼ3 times the upper limit of the reference range were identified, and their case records examined in detail.RESULTS -At baseline, 5.6% of the patients with type 2 diabetes (mean HbA 1c 8.5-9.0%) had serum ALT values between 1.0 and 2.5 times the upper limit of the reference range. On antidiabetic therapy, most of those patients (ϳ83%) had a decrease in ALT values, many into the normal range. The percentages of all patients with an on-therapy ALT value Ͼ3 times the upper limit of the reference range during double-blind and open-label treatment were as follows: rosiglitazone-treated 0.32%, placebo-treated 0.17%, and sulfonylurea-, metformin-, or insulintreated 0.40%. The respective rates of ALT values Ͼ3 times the upper limit of the reference range per 100 person-years of exposure were 0.29, 0.59, and 0.64.CONCLUSIONS -No evidence of hepatotoxic effects was observed in studies that involved 5,006 patients taking rosiglitazone as monotherapy or combination therapy for 5,508 personyears. This is in keeping with hepatic data from clinical trials of another member of the class, pioglitazone, and in contrast to the clear evidence of hepatotoxic effects observed during the troglitazone clinical trial program. These findings suggest that the idiosyncratic liver toxicity observed with troglitazone is unlikely to be a thiazolidinedione or a PPAR-␥ agonist class effect. Poorly controlled patients with type 2 diabetes may ...

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Section: Diabetes Care 25:815-821 2002mentioning

confidence: 83%

Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials

2002

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“…The major in vivo metabolites were similar to those observed in hepatocyte incubations and were M25, M16, and M20, all involving TZD-ring opening followed by methylation with and without oxidation. Thus, the major metabolism pathway for MK-0767 is very different from that of the other known TZD-containing PPAR agonists, troglitazone (Kawai et al, 1997), pioglitazone (Krieter et al, 1994;Maeshiba et al, 1997), and rosiglitazone (Bolton et al, 1996). TZD ring cleavage has been reported as a minor biotransformation pathway for troglitazone (Kassahun et al, 2001) and pioglitazone (Shen et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

IN VITRO METABOLISM OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL) PHENYL]METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST. I. ROLE OF CYTOCHROME P450, METHYLTRANSFERASES, FLAVIN MONOOXYGENASES, AND ESTERASES

Karanam¹,

Hop²,

Liu³

et al. 2004

Drug Metab Dispos

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The metabolism of MK-0767, (؎)-5-[(2,4-dioxothiazolidin-5-yl)-methyl]-2-methoxy-N-[[(4-trifluoromethyl) phenyl]methyl]benzamide, a thiazolidinedione (TZD)-containing peroxisome proliferatoractivated receptor ␣/␥ agonist, was studied in liver microsomes and hepatocytes from humans and rat, dog, and rhesus monkey, to characterize the enzyme(s) involved in its metabolism. The major site of metabolism is the TZD ring, which underwent opening catalyzed by CYP3A4 to give the mercapto derivative, M22. Other metabolites formed in NADPH-fortified liver microsomes included the TZD-5-OH derivative (M24), also catalyzed by CYP3A4, and the O-desmethyl derivative (M28), whose formation was catalyzed by CYP2C9 and CYP2C19. Metabolite profiles from hepatocyte incubations were different from those generated with NADPH-fortified microsomal incubations. In addition to M22, M24, and M28, hepatocytes generated several S-methylated metabolites, including the methyl mercapto (M25), the methyl sulfoxide amide (M16), and the methyl sulfone amide (M20) metabolites. Addition of the methyl donor, S-adenosyl methionine, in addition to NADPH, to microsomal incubations enhanced the turnover and resulted in metabolite profiles similar to those in hepatocyte incubations. Collectively, these results indicated that methyltransferases played a major role in the metabolism of MK-0767. Using enzyme-specific inhibitors, it was concluded that microsomal thiol methyltransferases play a more important role than the cytosolic thiopurine methyltransferase. Baculovirus-expressed human flavin-containing monooxygenase 3, as well as CYP3A4, oxidized M25 to M16, whereas further oxidation of M16 to M20 was catalyzed mainly by CYP3A4. Esterases were involved in the formation of the methyl sulfone carboxylic acids, minor metabolites detected in hepatocytes.

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“…This is somewhat different from the elimination of other TZDcontaining compounds like rosiglitazone (Bolton et al, 1996;Cox et al, 2000), pioglitazone (Krieter et al, 1994;Maeshiba et al, 1997), and troglitazone (Kawai et al, 1997). Interestingly, there have been several recent articles building on the work of Kassahun et al (2001) with TZD-ring scission of troglitazone.…”

Section: Discussionmentioning

confidence: 99%

Absorption, Metabolism, and Excretion of [¹⁴C]MK-0767 (2-Methoxy-5-(2,4-dioxo-5-thiazolidinyl)-N-[[4-(trifluoromethyl)phenyl] methyl]benzamide) in Humans

Kochansky

Rippley²,

Yan³

et al. 2006

Drug Metab Dispos

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circulating compound-related entity (>96% of radioactivity) through 48 h postdose. It was also found that ϳ91% of the total radioactivity area under the curve was due to intact MK-0767. Several minor metabolites were detected in plasma (<1% of radioactivity, each), formed by cleavage of the TZD ring and subsequent S-methylation and oxidation. All the metabolites excreted into urine were formed by TZD cleavage, whereas the major metabolite in feces was the O-demethylated derivative of MK-0767. Fig. 1), also known as KRP-297, is a thiazolidinedione (TZD)-containing compound that has been studied for the treatment of type 2 diabetes (Ballaux et al., 2006). In the same structural class as rosiglitazone and pioglitazone, MK-0767 is distinctly different from these compounds in that it binds to both ␣ and ␥ subtypes of the peroxisome proliferator-activated receptor (PPAR) with similar affinity (Murakami et al., 1998;Doebber et al., 2004), whereas rosiglitazone and pioglitazone were reported to bind primarily to the PPAR-␥ receptor (Lehmann et al., 1995;Forman et al., 1997). Binding to PPAR-␣ and -␥ results in increased expression of genes encoding proteins involved in glucose and lipid metabolism (Mudaliar and Henry, 2001). MK-0767 (2-methoxy-The purpose of the present study was to investigate the absorption, metabolism, and excretion of [ 14 C]MK-0767 in six male human volunteers. The in vitro metabolism of MK-0767 in nonclinical species and humans has been described previously (Karanam et al., 2004a,b;Liu et al., 2004;Reddy et al., 2004), whereas the in vivo metabolism in nonclinical species is the subject of a separate manuscript in preparation (S. Vincent, C. Kochansky, M. Creighton, G. Doss, B. Karanam, M. Wallace, C. Raab, H. Jenkins, R. Franklin, S. Chiu, H. Satoh, K. Awano, and M. Komuro, unpublished). The main biotransformation pathway of MK-0767 in human liver microsomes involves CYP3A4-mediated oxidative cleavage of the TZD ring, followed by S-methylation (catalyzed primarily by microsomal methyltransferase) to the methyl mercapto metabolite (M25) and subsequent S-oxidation (catalyzed by both CYP3A and flavin-containing monooxygenase) to methyl sulfoxide and sulfone amides (M16 and M20, respectively). In hepatocytes, M16, M20, and M25 are subject to esterase-mediated hydrolysis to the carboxylic acid analogs (Liu et al., 2004). Materials and Methods Chemicals

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The fate of a thiazolidinedione antidiabetic agent in rat and dog

Cited by 31 publications

References 4 publications

Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials

Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials

IN VITRO METABOLISM OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL) PHENYL]METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST. I. ROLE OF CYTOCHROME P450, METHYLTRANSFERASES, FLAVIN MONOOXYGENASES, AND ESTERASES

Absorption, Metabolism, and Excretion of [¹⁴C]MK-0767 (2-Methoxy-5-(2,4-dioxo-5-thiazolidinyl)-N-[[4-(trifluoromethyl)phenyl] methyl]benzamide) in Humans

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The fate of a thiazolidinedione antidiabetic agent in rat and dog

Cited by 31 publications

References 4 publications

Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials

Evaluation of Liver Function in Type 2 Diabetic Patients During Clinical Trials

IN VITRO METABOLISM OF MK-0767 [(±)-5-[(2,4-DIOXOTHIAZOLIDIN-5-YL)METHYL]-2-METHOXY-N-[[(4-TRIFLUOROMETHYL) PHENYL]METHYL]BENZAMIDE], A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR α/γ AGONIST. I. ROLE OF CYTOCHROME P450, METHYLTRANSFERASES, FLAVIN MONOOXYGENASES, AND ESTERASES

Absorption, Metabolism, and Excretion of [14C]MK-0767 (2-Methoxy-5-(2,4-dioxo-5-thiazolidinyl)-N-[[4-(trifluoromethyl)phenyl] methyl]benzamide) in Humans

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Absorption, Metabolism, and Excretion of [¹⁴C]MK-0767 (2-Methoxy-5-(2,4-dioxo-5-thiazolidinyl)-N-[[4-(trifluoromethyl)phenyl] methyl]benzamide) in Humans