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326 in thalassemia. The patients with 7/7 genotype appeared more prone to gallstone formation (100%) than those with 6/7 (47%) and 6/6 (41%) genotype. These results suggested that genetic polymorphisms in the key UGT1A1 enzyme family influence on serum bilirubin level in both groups of subjects. However the high incidence of gallstones in patients with 6/7 and 6/6 genotypes could be caused by other factor such as other site of mutation, food, environmental factors or pathophysiology in the patients. (Thai Journal of Pharmacology, Jan-Apr 2005, Vol.27, No.1, p. 60. Proceedings of 27 th Pharmacological and Therapeutic Society of Thailand Meeting, 17-18 March 2005.) EFFECTS OF UDP-GLUCURONOSYLTRANS- FERASE (UGT) 1A1 AND 1A6 POLYMORPHISMS ON ACETAMINOPHEN PHARMACOKINETICS IN THAI b-THALASSEMIA/HBE PATIENTS (NO. 861) Jeeranut Tankanitlert 1 , Thad A Howard 2 , Anusorn Temsakulphong 1 , Pornpan Sirankapracha 3 , Noppawan Phumala Morales 1 , Yupin Sanvarinda 1 , Pranee Fucharoen 3 , Russell E Ware 3 , Suthat Fucharoen 3 and Udom Chantharaksri 1 1 Department of Pharmacology, Faculty of Science, Mahidol University, 2 Division of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA, 3 Thalassemia Research Center, Institute of Science and Technology for Research and Development, Mahidol University, Bangkok, Thailand. Key words: Acetaminophen metabolism, UDP-glucuronosyltransferase, genetic polymorphism Pathophysiological changes and organ damage from iron overload can alter drug pharmacokinetics in patients with thalassemia, but genetic variations may also be important. Numerous drugs are metabolized by UDP-glucuronosyltransferase (UGT) enzymes including acetaminophen (paracetamol, PCM), a commonly available and widely used analgesic. UGT1A1 (UGT1A*28) promoter polymorphisms affect bilirubin metabolism and UGT1A6 polymorphisms (UGT1A6*2) also reduce enzymatic activity. These polymorphisms may contribute to the interindividual variations observed in PCM toxicity in the general population and in thalassemia. To elucidate the pharmacokinetics of PCM in thalassemia compared with normal subjects, peripheral blood DNA was extracted for UGT1A genotyping by fragment size and RFLP methods. Sixteen normal and nineteen thalassemic subjects were grouped according to UGT1A genotypes. After a single oral dose of 1000 mg PCM, drug disposition was determined by HPLC. In normal subjects, the UGT1A1*28 and UGT1A6*2 polymorphisms significantly decreased serum levels of PCM and its metabolites, while in thalassemic subjects only UGT1A6*2 had significant effects. This is the first pharmacogenetic study in thalassemia and the results indicate that these subjects might be more susceptible to unexpected side effects while taking therapeutic doses of PCM. Faculty of Science CHOLESTERYL LIONOLEATE IN LIPOPROTEINS: AN INDEX OF OXIDATIVE DAMAGE AND CLINICAL SEVERITY IN b-THALASSEMIA/HBE (NO. 862) Rataya Luechapudiporn 1, , Noppawan Phumala Morales 2 , Suthat Fucharoen 3 , Udom Chantharaksri 2 1 Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, 2 Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand. Key words : Cholesteryl esters, Oxidative damage, Thalassemia Serum markers of oxidative damage and cholesteryl esters were measured in lipoproteins of 30 β-thal/Hb E patients and compared with 10 healthy volunteers. Patients presented ironoverloading, a precipitous drop of α-tocopherol, and increased lipid peroxidation (TBARs) in both plasma and lipoproteins. Cholesteryl esters (CEs) in both LDL and HDL were separated and identified using HPLC. Cholesteryl linoleate, the most abundant CEs in lipoproteins was 70% lessen and some 50% reduction occurred to the others. The inverse relationship of the cholesteryl linoleate to cholesteryl oleate (CL/CO) ratios to the varying degrees of clinical severity suggested that the CL/CO ratio is an index of the damaged lipoproteins and may be used as a pathologic marker of the underlying iron overloading. A good correlation of NTBI and TBARs (r = 0.8, p < 0.01) in the LDL strongly support the contention of overloaded iron is responsible for initiating the lipid peroxidation in β-thal/Hb E. This study demonstrated that cholesteryl linoleate was the primary target of oxidative damage, induced by NTBI in the ?βthal/Hb E. It, thus, suggests that cholesteryl linoleate is the major target of oxidative damage in lipoproteins and may be used as a ‘severity index’ of the thalassemic syndrome. CONTINUOUS TRACKING TASK (CTT): THE RELATIONSHIP OF TIME ON TASK TO THE EFFECTS OF SEDATIVE DRUGS (NO. 863) Soo-amon S 1 , Johnsen S 2 , Wongwitdecha N 1 , Plasen S 1 , Hindmarch I 2 1 Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand, 2 HPRU Medical Research Centre, University of Surrey, Guildford, UK. The continuous tracking task (CTT) is a psychomotor task assessing sensorimotor coordination and divided attention. CTT tasks have been shown to be sensitive to the impairing effects of psychoactive drugs and are often used in studies assessing behavior following drug administration. The aim of this retrospective study was to investigate the relationship between test duration (7.5 or 10 min) and CTT performance following administration of alprazolam, lorazepam, promethazine and placebo. The results showed that alprazolam, lorazepam, and promethazine impaired performance on the CTT at 7.5 min and that a plateau was reached by 10 min for promethazine. In contrast, following placebo, performance on the PDF created with FinePrint pdfFactory Pro trial version http://www.pdffactory.com
Mahidol University Annual Research Abstracts, Vol. 33 327 CTT was stable at 7.5 min but had deteriorated by 10 min. These data suggest that performance on CTT tasks should take account of “time-on-task” as this appears to separate out drug induced impairment from task fatigue. (Thai Journal of Pharmacology, Jan-Apr 2005, Vol.27, No.1, p. 61. Proceedings of 27 th Pharmacological and Therapeutic Society of Thailand Meeting, 17-18 March 2005.) MODIFICATION OF PARAOXONASE AND PLATELET- ACTIVATING FACTOR ACETYL- HYDROLASE ACTIVITES IN HEMIN-INDUCED LIPOPROTEIN OXIDATION (NO. 864) Wongroganawong D, Chalermchoung C, Unchern S, Chantharaksri U, Phumala Morales N. Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400. Paraoxonase (PON) and platelet-activation factor acetylhydrolase (PAF-AH) are antioxidant enzymes associated with the HDL particle. Their functions are known to protect lipoproteins from oxidative modification. PON activity has been showed to be modified in oxidized HDL and in oxidative related diseases such as atherosclerosis. Although PAF-AH activity has been also reported to be modified in several diseases, there was no evidence related to the oxidative stress conditions. Hemin, a degradative product of hemoglobin, has been reported as a potent oxidative inducer of lipoproteins in vitro. It has become a prime suspect to be responsible for lipoprotein oxidation in thalassemic patients because of its high concentration in the serum of patients. This study was, therefore, aimed to study kinetic of hemin induced oxidation of lipoproteins on the modification of PON (in HDL) and PAF-AH (in LDL and HDL) activities. The results clearly demonstrated that PON was more susceptible to hemin-induced oxidative stress than PAF-AH. In HDL, PON activity was rapidly decreased within 1 hr after incubation with hemin. The activity of PON was continuously decreased. Its activity was remained only 30 % after 10 hr of the incubation. On the other hand, PAF-AH activity was unchanged in HDL but only slightly reduced in LDL, about 20% after 10 hr of incubation. Our results suggested that the loss of PON activity in hemin induced HDL oxidation may be relevant in vivo and could have and impact in thalassemia. (Thai Journal of Pharmacology, Jan-Apr 2005, Vol.27, No.1, p. 62. Proceedings of 27 th Pharmacological and Therapeutic Society of Thailand Meeting, 17-18 March 2005.) IN VIVO PHENOTYPING OF CY2A6 IN THAIS : COUMARIN VS NICOTINE (NO. 865) Peamkrasatam S 1,4 , Sriwatanakul K 1 , Wananukul V 2 , Sura T 2 , Chavalittumrong P 3 , Kamataki T 4 , Yoovathaworn K 1 1 Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok Thailand, 2 Department of Medicine, Faculty of Medicine at Ramathibodi Hospital, Mahidol University, Bangkok, Thailand, 3 Department of Medicine Science, Ministry of Public Health, Bangkok, Thailand, 4 Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Science, Hokkaido University, Sapporo, Japan. The association between the distribution characteristics of CYP2A6 catalytic activityies towards coumarin and nicotine was analyzed in 120 apparently healthy Thai volunteers. The probe drugs were given sequentially in the same subject with an approximate interval of one week, Urinary 7-hydroxycoumarin, plasma cotinine, and plasma nicotine were measured using HPLC assay. Genotyping for CYP2A6 gene of the subjects was also performed. The distribution of 7-OHC excreted in the subsequent 8-hr urine (0.03-15 mg) after a single oral administration of 15 mg coumarin (Venalot®) and cotinine/ nicotine ratio of the plasma concentrations (0.00-13.48) 2 hr after chewing a piece of nicotine chewing gum containing 2 mg nicotine (Nicorette®) showed clearly bimodality. However, the probit plot of cotinine/nicotine ratio in the plasma showed the higher number of apparent poor metabolizers (PM), in comparison to that of 7- OHC excreted in the urine. Despite the discordance in the number of PM subjects, a correlation between the in vivo dispositions of coumarin and nicotine was extremely close (R=0.92). No statistically significant difference in the CYP2A6 activities between male and female subjects was found. The results confirm that phenotyping of CYP2A6 using coumarin and that using nicotine are not metabolically equivalent. Ten subjects with known CYP2A6 genotypes were given a tablet of 15 mg coumarin again. Liver function test was investigated just before and24 hr after the coumarin administration. The results showed that coumarin at the challenging dose did not disturb the liver function even in the three subjects genotyped as CYP2A6*4/*4. Since the approximate half life of coumarin in human is only 2 hr, the probe drugs, therefore, could be theoretically given within two days consecutively. Even though both coumarin and nicotine can be clinically used as probe drugs in routine testing for CYP2A6 phenotype our results indicate that giving coumarin and nicotine sequentially to the same subject is a better protocol for a precise CYP2A6 phenotyping. (Thai Journal of Pharmacology, Jan-Apr 2005, Vol.27, No.1, p. 63. Proceedings of 27 th Pharmacological and Therapeutic Society of Thailand Meeting, 17-18 March 2005.) THE ACCUMULATION OF CADMIUM IN SNAKE- HEAD FISH (Ophicephalus striatus) FROM BANGKOK METROPOLITAN MARKETS. (NO. 866) Sarunya Laovitthayanggoon 1 , Auratai Aramphongphan 1, 2 , Lakana Himakhun 3 1 Toxicology Graduate Program, Faculty of Science, Mahidol University ; 2 Department of Pharmacology, Faculty of Science, Mahidol University ; 3 Department of Pathobiology, Faculty of Science, Mahidol University. Key words: Snakehead-fish, Cadmium and GFAAS The study was carried out to investigate the cadmium contamination in the various tissues (muscle, skin, gill and liver) of snakehead fish (Ophicephalus striatus), a fish with scales commonly found in Southeast Asia, which is economically important to Thailand. The samplings covered six Bangkok markets: Bangkok Noi, Ratchawat, Klongteoy, Yingchareon, Wongweanyai and Sainert markets. The cadmium level was measured by the Atomic Absorption Spectrophotometry (GFAAS). Results showed that the level of cadmium accumulation in muscle, skin, gill and liver were 0.02- 0.10, 0.02-0.07, 0.02-0.07 and 0.1-1.7 ppm (µg/g) respectively. The highest level was found in the liver especially at Bangkoknoi market, which was around 1.7 ppm (mg/kg.), which was 0.2 ppm more than PDF created with FinePrint pdfFactory Pro trial version http://www.pdffactory.com
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