Retraction Note to: Identification of CYP3A4 as the primary cytochrome P450 responsible for the metabolism of tandospirone by human liver microsomes.

The publisher has retracted this article [1] because it is an incorrect version that was published in error: Figures 5 and 6 are missing.

[Clinical evaluation of the risk factors for liver abscess after TACE or RFA].

Radiofrequency ablation(RFA)and transcatheter arterial chemoembolization (TACE) are widely enforced as a standard combined therapy for liver cancer. Liver abscess occurs occasionally as a complication. This clinical study was conducted to determine risk factors for liver abscess. We investigated the clinical background of 10 cases complicated by liver abscess in 957 cases of patients who underwent TACE or RFA for liver cancer at Minoh City Hospital between April 2002 and March 2012. Risk factors for liver abscess were analyzed statistically in comparison to a control group without liver abscess. Diabetes and a history of biliary tract organic disease were statistically significant independent risk factors determined by multivariate analysis. We consider patients with a history of biliary tract organic disease, or who have a potential biliary tract infection, and diabetes, to be susceptible to infection. A case presenting with diabetes and a history of biliary tract disease is in a high-risk group, so treatment with TACE or RFA for such cases should be considered carefully.

[Two cases of liver abscess caused by Clostridium perfringens after transcatheter arterial chemoembolization].

Case 1 involved a 74-year-old man. After transcatheter arterial chemoembolization( TACE) for hepatocellular carcinoma (HCC), abdominal computed tomography (CT) revealed a gas-containing lesion in the liver. The patient was diagnosed as having a gas-containing liver abscess, necessitating emergency drainage under laparotomy. Blood culture revealed Clostridium perfringens. He was discharged on day 63 after surgery. Case 2 involved a 70-year-old man who was admitted to our hospital for obstructive jaundice caused by HCC. He was treated with TACE after endoscopic retrograde biliary tract drainage (ERBD). On the second day, he was diagnosed as having a ruptured gas-containing liver abscess with massive hemolysis, necessitating emergency drainage under laparotomy. He died the next day after surgery. The clinical course of liver abscess caused by Clostridium perfringens can be fulminant and fatal with massive hemolysis.

[A case report of GIST of the small intestine with multiple liver abscesses].

We report a case of a woman in her fifties presenting with abdominal pain, headache and high fever. Blood examination showed a high CRP level and liver dysfunction, and then abdominal CT scan showed multiple liver masses and a 5 cm submucosal tumor of the small intestine. We diagnosed the multiple liver masses as liver abscesses, so we administered antibiotics. We suspected that the tumor was a cause of liver abscesses, and then performed a resection of the tumor and partial small intestine on the third day of hospitalization. We diagnosed the tumor as GIST because it was positive for c-kit and CD34 by immunohistochemistry. One of the resected liver nodules showed negative for c-kit and CD34, and we diagnosed it as a liver abscess. We performed percutaneous transhepatic abscess drainage (PTAD) because she ran into high fever after the operation, and then she recovered. We consider she has the possibility of liver metastasis, so we administered imatinib mesylate to her. No recurrence was found for 11 months after the operation. This case provides valuable information because there are few reports of GIST with liver abscesses.

Identification of CYP3A4 as the primary cytochrome P450 responsible for the metabolism of tandospirone by human liver microsomes.

The present study was carried out to characterize the human P450 isoforms involved in the metabolism of tandospirone, an anxiolytic agent known for its superior efficacy and safety. Among 11 yeast-expressed recombinant P450 isoforms tested, CYP2D6 and CYP3A4 exhibited the highest tandospirone metabolic activity. Although there was no qualitative difference between the two isoforms, a quantitative difference in metabolite profiling was found i.e., M4 (hydroxylation of the pyrimidine ring) was the major metabolite formed with CYP2D6 while M2 (hydroxylation of the norbornan ring) and 1-PP (oxidative cleavage of the butyl chain) predominated with CYP3A4. The metabolite profile on incubation with CYP3A4 was qualitatively and quantitatively similar to that obtained with human liver microsomes. In vitro intrinsic clearance (CLint) values derived from kinetic analysis using both P450 isoforms were similar (2.2 and 1.6 ml/min/nmol P450), but the hepatic content of CYP3A4 was found to be more abundant than that of CYP2D6. The in vitro metabolism of tandospirone by human liver microsomes was markedly inhibited by ketoconazole (a CYP3A4 inhibitor) but not by quinidine (a CYP2D6 inhibitor). These results indicate that the metabolism of tandospirone by human liver microsomes primarily involves CYP3A4, and to a lesser extent CYP2D6.

Identification of CYP3A4 as the primary cytochrome P450 responsible for the metabolism of tandospirone by human liver microsomes.

The present study was carried out to characterize the human P450 isoforms involved in the metabolism of tandospirone, an anxiolytic agent known for its superior efficacy and safety. Among 11 yeast-expressed recombinant P450 isoforms tested, CYP2D6 and CYP3A4 exhibited the highest tandospirone metabolic activity. Although there was no qualitative difference between the two isoforms, a quantitative difference in metabolite profiling was found i.e., M4 (hydroxylation of the pyrimidine ring) was the major metabolite formed with CYP2D6 while M2 (hydroxylation of the norbornan ring) and 1-PP (oxidative cleavage of the butyl chain) predominated with CYP3A4. The metabolite profile on incubation with CYP3A4 was qualitatively and quantitatively similar to that obtained with human liver microsomes. In vitro intrinsic clearance (CLint) values derived from kinetic analysis using both P450 isoforms were similar (2.2 and 1.6 ml/min/nmol P450), but the hepatic content of CYP3A4 was found to be more abundant than that of CYP2D6. The in vitro metabolism of tandospirone by human liver microsomes was markedly inhibited by ketoconazole (a CYP3A4 inhibitor) but not by quinidine (a CYP2D6 inhibitor). These results indicate that the metabolism of tandospirone by human liver microsomes primarily involves CYP3A4, and to a lesser extent CYP2D6.

In vitro drug-drug interactions with perospirone and concomitantly administered drugs in human liver microsomes.

In vitro metabolism studies were conducted to assess drug-drug interactions between perospirone, an antipsychotic agent, and concomitantly administered drugs--biperiden, flunitrazepam, haloperidol, and diazepam--using human liver microsomes. The metabolism of perospirone in the presence of 100 microg/ml drugs was decreased to 45-73% of that in their absence, whereas no effects were observed with any of the drugs at 1 microg/ml or lower. The effects of perospirone on the metabolism of concomitantly administered drugs were also assessed, and no inhibitory effect was observed. Thus, the metabolism of perospirone and concomitantly administered drugs did not demonstrate any marked mutual inhibition in the human liver microsomes. On the other hand, the perospirone metabolism was markedly reduced by ketoconazole indicating a major role for CYP 3A4. Based on the inhibition constant (Ki) for perospirone metabolism and the plasma unbound concentration of ketoconazole, in vivo perospirone clearance was estimated to be reduced to 64-90% of the control level. Thus careful attention should be paid to the possibility of increase in unchanged perospirone concentration when perospirone is co-administered with drugs that are known as CYP3A4 inhibitors, including macrolide antibiotics and other imidazole antifungals.

In vitro metabolism of perospirone in rat, monkey and human liver microsomes.

In vitro metabolism of perospirone was examined with rat, monkey and human liver S9, human liver microsomes and yeast microsomes expressing human P450, using 14C labeled perospirone. With rat liver S9, the major metabolites were MX9 and ID-11614, produced by cleavage at the butylene chain. However, some butylene non-cleavage and hydration of the cyclohexane ring were found, although limited in extent. Unknown metabolites accounted for about 10% of the total. After incubation for 10 minutes with monkey liver S9, the major metabolites were ID-15036 and MX11, hydrated in the cyclohexane ring. After incubation for 60 minutes, ID-15001, i.e. the butylene chain cleavage type increased. Unknown metabolites accounted for about 20%. After incubation for 10 minutes with human liver S9, the major metabolite was ID-15036, hydrated in the cyclohexane ring. In addition, MX11 and many unknown metabolites were evident. After incubation for 60 minutes, the butylene chain cleavage type and unknown metabolites increased. Individual differences were found in the metabolic reaction rate. With human liver microsomes. MX11, ID-15001 and unknown metabolites were again the major metabolites. With yeast microsomes expressing human P450 subtypes, CYP1A1, 2C8, 2D6, 3A4 were responsible for the metabolism in particular, and CYP3A4 contributes greatly. Therefore it is unlikely that genetic polymorphism will arise a present a problem with regard to the clinical drug. The results demonstrated that the main metabolic pathway in human liver S9 and liver microsomes involve oxidation at cyclohexane, oxidative cleavage of the butylene side chain and S-oxidation. The same was the case in rat and monkey S9, but species differences were found in the proportions of the metabolites produced.