N-acetyltransferase 2 genotype-related sulfapyridine acetylation and its adverse events

Sulfapyridine (SP), one of the metabolites of sulfasalazine (SASP), is further metabolized into N-acetylsulfapyridine (AcSP) by polymorphic N-acetyltransferase 2 (NAT2). NAT2 activity has been diagnosed by phenotyping, that is, evaluating plasma concentrations or urinary excretions of tentatively administered test drugs for dose individualization and avoidance of serious adverse events. Herein, we investigated the relationship between NAT2 genotypes and the pharmacokinetics of SP in healthy Japanese subjects, as well as the adverse events of SASP in patients with inflammatory bowel disease (IBD). Eight healthy subjects and 13 IBD patients were classified into three groups by NAT2 genotyping; the homozygote for the wild-type allele (Rapid Types), the compound heterozygote for the wild-type and mutant alleles (Intermediate Types), and the homozygote for mutant alleles (Slow Types). A single oral dose of 40 mg/kg SASP was administered to each healthy subject, and plasma and urine samples were taken until 51 and 72 h after administration, respectively. Both the SP and AcSP concentrations in each sample were determined by the HPLC method. The NAT2 genotypes were well-correlated with the plasma concentrations or urinary excretions of SP and AcSP in 8 healthy subjects, except for one Slow Type. In patients with IBD, skin rash was seen in 3 of 6 Rapid Types and 1 of 6 Intermediate Types, consistent with the concept that hypersensitive reactions are independent of serum SP concentrations. In contrast, SASP dosing-related acute pancreatitis was found in the Slow Type patient. In this case, the NAT2 activity was diagnosed by genotyping in advance, and the medical staff could pay scrupulous attention, resulting in no serious subjective symptoms such as abdominal pain, anorexia or fever. Further investigations on the relationship between the NAT2 genotype and adverse events are required, although genotyping appeared to be a promising method to avoid such serious adverse events.     

MDR1 genotype-related pharmacokinetics and pharmacodynamics

The multidrug resistant transporter MDR1/P-glycoprotein, the gene product of MDR1, is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily of membrane transporters. MDR1 acts as an energy-dependent efflux pump that exports its substrates out of cells. MDR1 was originally isolated from resistant tumor cells as part of the mechanism of multidrug resistance, but over the last decade, it has been elucidated that human MDR1 is also expressed throughout the body to confer intrinsic resistance to the tissues by exporting unnecessary or toxic exogeneous substances or metabolites. A number of structurally unrelated drugs are substrates for MDR1, and MDR1 and other transporters are recognized as an important class of proteins for regulating pharmacokinetics and pharmacodynamics. In 2000, Hoffmeyer et al. performed a systemic screening for MDR1 polymorphisms and detected 15 single nucleotide polymorphisms (SNPs). They also indicated that a polymorphism in exon 26 at position 3435 (C3435T), a silent mutation, affected the expression level of MDR1 protein in duodenum, and thereby the intestinal absorption of digoxin. To date, the genotype frequencies of C3435T have been investigated extensively using a larger population and interethnic difference has been elucidated, and a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical studies on MDR1 genotype-related MDR1 expression and pharmacokinetics have also been performed around the world; however, results were not always consistent with Hoffmeyer's report. In this review, published reports are summarized for the future individualization of pharmacotherapy based on MDR1 genotyping. In addition, recent investigations have raised the possibility that MDR1 and related transporters play a fundamental role in regulating apoptosis and immunology, and in fact, there are reports of MDR1-related susceptibility to inflammatory bowel disease, HIV infection and renal cell carcinoma. Herein, these issues are also summarized, and the current status of the knowledge in the area of pharmacogenomics of other transporters is briefly introduced.     

Effects of St John's wort and hypericin on cytotoxicity of anticancer drugs

St John's wort (SJW) is Hypericum perforatum L., Hypericaceae, a herbaceous perennial plant native to Europe and Asia, and its various preparations are widely used for the treatment of mild-to-moderately severe depressive disorders. With increasingly prevalent use, the interactions with SJW preparations with co-administered drugs have been reported, presumably via MDR1-mediated processes. In this paper, the effects of SJW extract on antiproliferative effects of anticancer drugs and the expression of MDR1 mRNA were examined using HeLa and its MDR1-overexpressing subline. The effects on MDR1-mediated transport were also evaluated using [(3)H]digoxin and LLC-GA5-COL150 cells, which were established by transfection of human MDR1 cDNA into porcine kidney epithelial LLC-PK(1) cells. The content of hypericin, a presumed active moiety within SJW extract, was determined by HPLC with a photo diode array to be 0.085 (w/w)%, and the effects of hypericin were also evaluated and compared with those of SJW extract. It was concluded that SJW extract reversed the cytotoxicity of paclitaxel and slightly of daunorubicin, down-regulated MDR1 mRNA, and inhibited MDR1-mediated transport, presumably due to other components than hypericin.     

Pharmacogenetics of intestinal absorption

The small intestine is the primary site of absorption for many drugs administered orally and so is the target tissue for pharmacotherapeutic strategies to control the oral absorption of drugs. Drug transporters, including the ATP-binding cassette (ABC) superfamily and the solute carrier (SLC) superfamily, have been considered to play a physiological role in regulating the absorption of xenobiotics, and variations in their expression level and function in the small intestine cause intra- and inter-individual variation in the oral absorption of drugs. Recent advances in molecular biology have suggested that genetic polymorphisms are associated with the expression level and function, and thereby inter-individual variation. In this review, the pharmacogenetics of these transporters is summarized, and their future significance in the clinical setting is discussed.     

Complications of radiofrequency ablation for hepatocellular carcinoma in a multicenter study: An analysis of 16 346 treated nodules in 13 283 patients

Aim: We surveyed multiple centers to identify types and frequency of complications and mortality rate associated with radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC). Methods: We distributed a questionnaire developed by members of the Chugoku‐Shikoku Society for the Local Ablation Therapy of Hepatocellular Carcinoma to 20 centers and analyzed types and frequency of complications and mortality rate. Results: In total, 16 346 nodules were treated in 13 283 patients between January 1999 and November 2010. Five patients (0.038%) died: two from intraperitoneal hemorrhage, and one each from hemothorax, severe acute pancreatitis and perforation of the colon. In 16 346 treated nodules, 579 complications (3.54%) were observed, including 78 hemorrhages (0.477%), 276 hepatic injuries (1.69%), 113 extrahepatic organ injuries (0.691%) and 27 tumor progressions (0.17%). The centers that treated a large number of nodules and performed RFA modifications, such as use of artificial ascites, artificial pleural effusion and bile duct cooling, had low complication rates. Conclusion: This study confirmed that RFA is a low‐risk treatment for HCC and that sufficient experience and technical skill can reduce complications.