Sang-Seop Lee

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of fexofenadine in relation to the MDR1 genetic polymorphism

Our objective was to evaluate the effect of itraconazole, a P‐glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of fexofenadine, a P‐glycoprotein substrate, in relation to the multidrug resistance 1 gene (MDR1) G2677T/C3435T haplotype.

Genetic polymorphisms in Na+-taurocholate co-transporting polypeptide (NTCP) and ileal apical sodium-dependent bile acid transporter (ASBT) and ethnic comparisons of functional variants of NTCP among Asian populations

Genetic variants of Na+-taurocholate co-transporting polypeptide (NTCP; SLC10A1) and ileal apical sodium-dependent bile acid transporter (ASBT; SLC10A2), which greatly contribute to bile acid homeostasis, were extensively explored in the Korean population and functional variants of NTCP were compared among Asian populations. From direct DNA sequencing, six SNPs were identified in the SLC10A1 gene and 14 SNPs in the SLC10A2 gene. Three of seven coding variants were non-synonymous SNPs: two variants from SLC10A1 (A64T, S267F) and one from SLC10A2 (A171S). No linkage was analysed in the SLC10A1 gene because of low frequencies of genetic variants, and the SLC10A2 gene was composed of two separated linkage disequilibrium blocks contrary to the white population. The stably transfected NTCP-A64T variant showed significantly decreased uptakes of taurocholate and rosuvastatin compared with wild-type NTCP. The decreased taurocholate uptake and increased rosuvastatin uptake were shown in the NTCP-S267F variant. The allele frequencies of these functional variants were 1.0% and 3.1%, respectively, in a Korean population. However, NTCP-A64T was not found in Chinese and Vietnamese subjects. The frequency distribution of NTCP-S267F in Koreans was significantly lower than those in Chinese and Vietnamese populations. Our data suggest that NTCP-A64T and -S267F variants cause substrate-dependent functional change in vitro, and show ethnic difference in their allelic frequencies among Asian populations although the clinical relevance of these variants is remained to be evaluated.

Robust CYP2D6 genotype assay including copy number variation using multiplex single-base extension for Asian populations

BACKGROUND We developed a CYP2D6 genotyping method that includes copy number variation (CNV) and recently known functional haplotypes using multiplex single-base extension (SBE). METHODS Twelve CYP2D6 alleles (*1, *2, *5, *10, *14, *18, *21, *41, *49, *52, *60, and a duplication of CYP2D6) were genotyped using 2 PCR reactions followed by multiplex SBE with 10 primers and singleplex SBE with 1 primer. The result from 758 Korean samples was validated by comparison with the results of direct sequencing or other genotyping methods. We also genotyped 89 Chinese and 122 Vietnamese subjects to determine the presence of recently identified functional alleles. RESULTS All 12 CYP2D6 alleles, including gene deletion and duplication, were obviously discriminated. The concordance rate was 100% between our method and other methods. Our method also covered over 98% of the CYP2D6 genotypes in Japanese and Chinese subjects based on reported data. In addition to published genotypes, *14, *21, *41, *49, and *52 were found in about 5% in Chinese and Vietnamese. CONCLUSIONS The CYP2D6 genotyping method may be clinically applicable for Asian populations. The method can be improved easily to cover other ethnic groups by utilizing additional haplotype tagging SNPs.

Primary aneurysmal bone cyst of the patella: a case report.

Aneurysmal bone cysts account for less than 1% of primary bone tumours and have a predilection for the metaphyses of the long bones of the leg. Only 1% of all aneurysmal bone cysts occur in the patella. We report on a 30-year-old man with a primary aneurysmal bone cyst in the right patella treated with curettage. The defect was filled with demineralised bone matrix and allogeneic cancellous bone graft. At the 1.5-year follow-up, the bone graft was well incorporated, the patient experienced no pain or tenderness and had a full range of knee movement.

NEUROTOXIC PYRIDINIUM METABOLITES OF HALOPERIDOL ARE SUBSTRATES OF HUMAN ORGANIC CATION TRANSPORTERS

Two neurotoxic pyridinium metabolites of haloperidol, 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxybutyl]pyridinium ion (HPP+) and 4-(4-(chlorophenyl)-1–4-(fluorophenyl)-4-hydroxybutyl-pyridinium (RHPP+), are formed in the liver and found in the brain. To understand how these neurotoxic pyridinium metabolites are distributed in the brain, HPP+ and RHPP+ were evaluated as substrates for human organic cation transporters (hOCTs). Both HPP+ and RHPP+ were accumulated in Caco-2 cells, and these accumulations were significantly inhibited by pretreatment with the hOCT inhibitors verapamil, cimetidine, phenoxybenzamine, and corticosterone. The contribution of each hOCT was evaluated based on measurements of the intracellular concentrations of haloperidol metabolites in Madin Darby canine kidney (MDCK) cells transfected with hOCT1, hOCT2, or hOCT3. HPP+ accumulated in hOCT-overexpressing MDCK cells in a concentration-dependent manner, with estimated Km values of 0.99, 2.79, and 2.23 μM and Vmax values of 282.1, 256.1, and 400.2 pmol/min/μg protein for hOCT1, hOCT2, and hOCT3, respectively. RHPP+ accumulated in hOCT1- and hOCT3-overexpressing MDCK cells, with estimated Km values of 5.15 and 8.21 μM and Vmax values of 1230.9 and 1348.6 pmol/min/μg protein for hOCT1 and hOCT3, respectively. On the other hand, RHPP+ did not accumulate in the hOCT2-expressing MDCK cells. These results suggest that HPP+ and RHPP+ are substrates for hOCTs, with the exception of RHPP+ for hOCT2. Thus, hOCTs seem to contribute to the disposition of these toxic metabolites in human subjects, although further in vivo studies are required to elucidate the involvement of hOCTs in the disposition of haloperidol pyridinium metabolites.

Itraconazole and rifampin alter significantly the disposition and antihistamine effect of ebastine and its metabolites in healthy participants.

The present study was performed to elucidate the effects of itraconazole and rifampin on the pharmacokinetics and pharmacodynamics of ebastine, a nonsedative H1 receptor antagonist. In a 3‐way crossover sequential design with 2‐week washouts, 10 healthy participants were pretreated with itraconazole for 6 days, rifampin for 10 days, or neither. After oral administration of 20 mg ebastine, blood and urine samples were collected for 72 and 24 hours, respectively, and histamine‐induced wheal and flare reactions were measured to assess the antihistamine response for 12 hours. Itraconazole pretreatment decreased the oral clearance of ebastine to 10% (P < .001) and increased the AUC∞ of the active metabolite, carebastine, by 3‐fold (P < .001). On the other hand, rifampin pretreatment decreased the AUC∞ of carebastine to 15% (P < .001), with an enormous reduction in the oral bioavailability of ebastine and significantly reduced histamine‐induced skin reactions. From these results, the disposition of ebastine and carebastine seems to be significantly altered by coadministration of itraconazole or rifampin. The antihistamine response after ebastine dosing would be decreased following rifampin pretreatments.

Effects of clopidogrel and clarithromycin on the disposition of sibutramine and its active metabolites M1 and M2 in relation to CYP2B6*6 polymorphism.

Plasma concentrations of sibutramine and its two active metabolites after single oral dose of sibutramine were determined in Korean healthy male subjects with different CYP2B6 genotypes (CYP2B6*1/*1, *1/*6 and *6/*6), either alone or after four-day pretreatment with clopidogrel or clarithromycin. The pretreatment with clopidogrel and clarithromycin raised the mean area under the concentration–time curve (AUC) of sibutramine by 163% and 255%, respectively. Co-administration of clarithromycin, combined with CYP2B6*6/*6 genotype, led to highest concentration of sibutramine. The molar sum AUC (M1 + M2) was raised by 35% in the clopidogrel phase but not significantly affected by clarithromycin or CYP2B6 genotype. The CYP2B6*6/*6 subjects in the clopidogrel phase showed the highest molar AUC (M1 + M2) among three genotype groups throughout the three phases. The exposure of sibutramine and its metabolites seemed to be associated with the CYP2B6 genotype. The treatment of clopidogrel significantly altered the disposition of active metabolites as well as sibutramine, but clarithromycin only affects the disposition of sibutramine. These results suggest that the perturbation of CYP2B6 activity may contribute to the inter-individual variation of sibutramine drug responses although the clinical relevance is remained to be established.

Temperature Control for LED Lamps Using RF Communication

In this paper, a temperature control for LED (light emitting diode) lamp using a cooling fan is studied. An efficient temperature control scheme for the LED lamp using the fan wind at the lowest sound noise is studied. For the study, after measurement of the minimum sound noise of the fan and related temperature of the LED lamp through tests, experiments on temperature control of the LED lamp using the fan with various size of heat sinks was performed. To reduce the fan sound noise, a method of reducing the operation time with optimal size of the heat sink was studied. Also, a control of LED lamps using RF communication was studied.