We tested the hypothesis that a force reduction in hyperthyroid rat soleus muscle would be associated with oxidative modification in myosin heavy chain (MHC). Daily injection of thyroid hormone [3,5,3'-triiodo-L-thyronine (T3)] for 21 days depressed isometric forces of whole soleus muscle across a range of stimulus frequencies (P < 0.01). In fiber bundles, hyperthyroidism also led to pronounced reductions (P < 0.01) in both K+ - and 4-chloro-m-cresol-induced contracture forces. The degrees of the reductions were similar between these two contractures that were induced by distinct reagents. Treatment with T3 elicited a significant decrease ( approximately 14%; P < 0.05) in the relative content of MHC contained in myofibrillar proteins. The content of carbonyl groups in myofibrillar protein extracts was elevated (P < 0.05) by approximately 50% in T3-treated muscles. Immunoblot analyses on T3-treated muscles showed a greater increase (106%; P < 0.05) of the carbonyl content in MHC than in myofibrillar protein extracts. These data suggest that in hyperthyroidism the decrease in force production of skeletal muscles may stem primarily from failure in myofibrillar protein function resulting from oxidative modification of MHC.

ABSTRACT:This prospective study is designed to examine the effects of severe renal failure on the pharmacokinetics of irinotecan. The pharmacokinetics of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), and SN-38 glucuronide (SN-38G) in three cancer patients with severe renal failure [creatinine clearance (Ccr) <20 ml/min] who were undergoing dialysis and received 100 mg/m 2 irinotecan as monotherapy were prospectively compared with those in five cancer patients with normal renal function (Ccr >60 ml/min). To ensure that the subjects had similar genetic backgrounds of UDPglucuronosyltransferase (UGT) 1A1, patients with UGT1A1*1/*1, IntroductionSeveral lines of evidence have demonstrated that severe renal failure differentially affects drug uptake or efflux transporters and drug-metabolizing enzymes in the liver. Even drugs that are predominantly eliminated by hepatic transport and metabolism can be affected by severe renal failure, leading to unexpected consequences, such as atypical pharmacokinetics and an increased risk of adverse drug reactions. High levels of uremic toxins in such patients are partially implicated in these effects (Nolin et al., 2008).Irinotecan is extensively metabolized in the liver to an active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), by carboxylesterase, which is then conjugated predominantly by liver UDPglucuronosyltransferase (UGT) 1A1 to form inactive SN-38 glucuronide (SN-38G) (chemical structures; http://www.pharmgkb.org/ search/pathway/irinotecan/metabolites.html). Polymorphisms in UGT1A1 gene, such as UGT1A1*28 and *6, can cause reduced glucuronidation of SN-38, thus resulting in severe irinotecaninduced toxicity. UGT1A1*6/*6, *28/*28, and *6/*28 genotypes have been linked to significantly decreased conversion of SN-38 to SN-38G and severe neutropenia in Asians (Minami et al., 2007).Transporters expressed in the liver are also implicated in the pharmacokinetics of irinotecan and its metabolites. The uptake of SN-38 from the systemic circulation by hepatocytes is mediated by organic anion transporter peptide 1B1 (OATP1B1) (Nozawa et al., 2005). ATP-binding cassette transporters such as ABCC2, ABCB1, and ABCG2 govern the biliary excretion of irinotecan and its metabolites (http://www.pharmgkb.org/do/serve?objId ϭ PA2001&objCls ϭ Pathway).Because irinotecan is extensively metabolized and transported in the liver, attention has been focused on the hepatic factors underlying interpatient variability in pharmacokinetics of irinotecan. Studies examining the pharmacokinetics of irinotecan in renally impaired patients are scant. The pharmacokinetics of irinotecan in patients with mild renal impairment who had a creatinine clearance (Ccr) of 35 to 66 ml/min were similar to those in patients with normal renal function (de Jong et al., 2008). Although several case reports have examined the effects of more severe renal dysfunction requiring dialysis on the pharmacokinetics or toxicity of irinotecan (Venat-Bouvet et al., 2007;Czock et al., 2009), no prospective study has been per...

We found that nilotinib is a potent noncompetitive inhibitor of human UGT1A1 activity.

ABSTRACT:Sorafenib and sunitinib are novel small-molecule molecularly targeted anticancer drugs that inhibit multiple tyrosine kinases. These medicines have shown survival benefits in advanced renal cell carcinomas as well as in advanced hepatocellular carcinomas and gastrointestinal stromal tumors, respectively. The effects of sorafenib and sunitinib on midazolam 1-hydroxylation catalyzed by human CYP3A4 or CYP3A5 were investigated. Sorafenib and sunitinib inhibited metabolic reactions catalyzed by recombinant CYP3A4. Midazolam hydroxylation was also inhibited in human liver microsomes harboring the CYP3A5*3/*3 genotype (poor CYP3A5 expressor). In contrast, midazolam 1-hydroxylation catalyzed by recombinant CYP3A5 was enhanced by the coexistence of sorafenib or sunitinib in a concentration-dependent manner, with saturation occurring at approximately 10 M. Midazolam hydroxylation was also enhanced in human liver microsomal samples harboring the CYP3A5*1/*1 genotype (extensive CYP3A5 expressor).Sorafenib N-oxidation and sunitinib N-deethylation, the primary routes of metabolism, were predominantly catalyzed by CYP3A4 but not by CYP3A5. The preincubation period of sorafenib and sunitinib before the midazolam addition in the reaction mixture did not affect the enhancement of CYP3A5-catalyzed midazolam hydroxylation, indicating that the enhancement was caused by parent sorafenib and sunitinib. Docking studies with a CYP3A5 homology model based on the structure of CYP3A4 revealed that midazolam closely docked to the heme of CYP3A5 compared with sorafenib or sunitinib, suggesting that these anticancer drugs act as enhancers, not as substrates. Our results thus showed that sorafenib and sunitinib activated midazolam 1-hydroxylation by CYP3A5 but inhibited that by CYP3A4. Unexpected drug interactions involving sorafenib and sunitinib might occur via heterotropic cooperativity of CYP3A5.

No abstract