To examine the mechanism accounting for the diverse alteration of hepatic metabolism of CYP3A substrates observed with renal function being severely impaired, the hepatic drug metabolizing activity was evaluated using liver microsomes prepared from rats with glycerol-induced acute renal failure (ARF). Midazolam, nifedipine and rifabutin were employed as representative CYP3A substrates. When the Michaelis-Menten parameters, K(m) and V(max) , were examined in the incubation study, the K(m) values of midazolam and nifedipine in ARF rats were shown to decrease by 50.9% and 29.9% compared with the normal value, respectively. The V(max) values of midazolam and nifedipine in ARF rats also decreased by 49.3% and 28.0%, respectively, showing that their decreased K(m) values accompanied the decreased V(max) values. The parameters of nifedipine seemed to alter to a lesser extent than those of midazolam. As for rifabutin metabolism, the decrease in the K(m) value was observed in ARF rats, but it did not accompany the decrease in the V(max) value. Then, the hepatic expressions of the CYP3A subfamily were examined with western blotting using anti-CYP3A1 and anti-CYP3A2 antibodies. It was revealed that the hepatic expression of CYP3A2 decreased, while that of CYP3A1 was unaffected. Additionally, a band signal deduced to originate from CYP3A9 was clearly detected in ARF, but not in normal rats. Considering each substrate having different specificities for CYP3A subfamily member proteins, individual alterations of hepatic CYP3A subfamily expression seem to underlie the diverse alterations of hepatic metabolism of CYP3A substrates in ARF rats.
The effect of carrageenan-induced acute peripheral inflammation (API) on the pharmacokinetics of the hepatically metabolizing compound midazolam (MDZ) was investigated in rats. Rats were subcutaneously treated with λ-carrageenan in the hind paw to induce API. When MDZ was intravenously administered in male rats, it was demonstrated that the plasma concentration profile of MDZ slightly alters in API rats compared with that in normal rats, while the plasma concentrations of its metabolites, 4-hydroxy and 1'-hydroxy MDZ, are markedly reduced with delayed appearances in API rats. In the incubation study with rat liver microsomes, it was clearly indicated that the generation rates of the two metabolites decrease in API rats. Western blot analysis revealed that hepatic CYP3A1 expression increases, while CYP3A2 expression decreases in API rats. In female rats, in which CYP3A2 is barely expressed in the liver, MDZ metabolism is little affected by API. These findings indicate that the hepatic handling of a therapeutic compound varies with API, largely due to altered hepatic expression of the drug-metabolizing enzyme.
Cisplatin is commonly used for esophageal and gastric cancer, however, the agent has high emetic risk, classified as highly emetic chemotherapy. Ohtsu et al. demonstrated in patients with advanced gastric cancer that 5-fluorouracil (5-FU) plus cisplatin led to a significantly higher tumor response rate and longer median progression-free survival but not overall survival as compared with 5-FU alone (1). Koizumi et al. also reported in phase 3 study comparing the effect of S-1 alone and its combination with cisplatin in patients with advanced gastric cancer that the combination was superior to S-1 alone in prolonging median progression-free survival (HR: 0.57; p<0.0001) as well as median overall survival (HR: 0.77; p=0.04) but led to more severe adverse drug reactions, including nausea and vomiting (2). Thus, oral fluoropyrimidine and cisplatin combination chemotherapy is currently used as the first-line treatment option for unresectable advanced gastric cancer. On the other hand, Bang et al. reported in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric or gastro-oesophageal junction cancer that addition of trastuzumab (monoclonal antibody to HER2) to chemotherapy led to ignificantly longer median overall survival than chemotherapy alone (3). Thus, oral fluoropyrimidine, cisplatin and trastuzumab combination chemotherapy is currently regarded as the standard chemotherapy for HER2-positive gastric cancer.On the other hand, cisplatin with 5-FU regimen is recommended as neoadjuvant chemotherapy for stage II/III thoracic esophageal cancer and unresectable progressive recurrent esophageal cancer (4, 5).Cisplatin is classified as chemotherapy with high emetic risk (HEC) in several guidelines for prevention of chemotherapy-induced nausea and vomiting (CINV) (6-9).
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