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Interethnic variability of warfarin maintenance requirement is explained by VKORC1 genotype in an Asian population

Lee SC, Ng SS, Oldenburg J, Chong PY, Rost S, Guo JY, et al.

Clin. Pharmacol. Ther., 2006 Mar;79(3):197-205.
PMID: 16513444

Chinese and Malay subjects have been reported to require less maintenance warfarin than Indians that could not be accounted for by cytochrome P450 (CYP) 2C9 variants. Vitamin K epoxide reductase complex 1 (VKORC1) is the target enzyme of warfarin, and VKORC1 intronic variants and haplotypes have recently been shown to influence VKORC1 activity and warfarin requirements.

Matched MeSH terms: Cytochrome P-450 CYP2C9
In vitro effects of active constituents and extracts of Orthosiphon stamineus on the activities of three major human cDNA-expressed cytochrome P450 enzymes

Pan Y, Abd-Rashid BA, Ismail Z, Ismail R, Mak JW, Pook PC, et al.

Chem Biol Interact, 2011 Mar 15;190(1):1-8.
PMID: 21276781 DOI: 10.1016/j.cbi.2011.01.022

Orthosiphon stamineus (OS) has been traditionally used to treat diabetes, kidney and urinary disorders, high blood pressure and bone or muscular pain. To assess the possibility of drug-herb interaction via interference of metabolism, effects of four OS extracts of different polarity and three active constituents (sinensetin, eupatorin and rosmarinic acid) on major human cDNA-expressed cytochrome P450 (CYP) enzymes were investigated. Three substrate-probe based high-performance liquid chromatography (HPLC) assays were established to serve as activity markers for CYP2C9, CYP2D6 and CYP3A4. Our results indicate that OS extracts and constituents exhibited differential modulatory effects on different CYPs. While none of the OS components showed significant inhibition on CYP2C9, eupatorin strongly and uncompetitively inhibited CYP2D6 activity with a K(i) value of 10.2μM. CYP3A4 appeared to be the most susceptible enzyme to OS inhibitory effects. It was moderately inhibited by OS dichloromethane and petroleum ether extract with mixed-type and noncompetitive inhibitions (K(i)=93.7 and 44.9μg/mL), respectively. Correlation study indicated that the inhibition was accounted for by the presence of eupatorin in the extracts. When IC(50) values of these extracts were expressed in volume per dose unit to reflect inhibitory effect at recommended human doses from commercially available products, moderate inhibition was also observed. In addition, CYP3A4 was strongly and noncompetitively inhibited by eupatorin alone, with a K(i) value of 9.3μM. These findings suggest that co-administration of OS products, especially those with high eupatorin content, with conventional drugs may have the potential to cause drug-herb interactions involving inhibition of major CYP enzymes.

Matched MeSH terms: Cytochrome P-450 CYP2C9
Fulltext Pharmacogenomics in drug therapy and interaction: the role of cytochrome P450

Ong, Chin-Eng, Yan, Pan, Tiong, Kai-Hung, Yiap, Beow-Chin, Tan, Eng-Lai, Pook, Peter, et al.

International e-Journal of Science, Medicine & Education, 2008;2(3):-.
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Pharmacogenomics (or pharmacogenetics), the study of the effects of genetic differences on a person’s response to drugs, can help in optimizing drug efficacy and minimizing adverse drug reactions. Interperson difference in drug metabolism is one of the important consequences of such genetic variation. This variation is determined in part by mutations in cytochrome P450 enzymes (CYPs). IMU is part of a major collaborative research project in the area of phamacogenetics and drug metabolism. Working together with USM and UiTM, our group has, since 2000, generated useful population database on genetic polymorphism of various CYP isoforms. We have successfully genotyped three major ethnic groups, Malay, Indian and Chinese for their allelic frequency of important isoforms. These include CYP2D6, CYP2C9, CYP2C8 and CYP2A6. Data generated so far collectively have contributed to our effort in mapping and constructing genomic database for Malaysian population.
Since early 2002, our research has been focusing on developing in vitro methods in studying the functional consequences of genetic polymorphism of CYP enzymes. Using site-directed mutagenesis, CYP mutants, carrying nucleotide changes as reported in known alleles in human populations, were generated and expressed in E. coli system, and the expressed recombinant proteins were characterized using enzyme assays to determine the functional consequences of mutations. We have established a series of HPLC (high performance liquid chromatography)-based and fluorescence-based assays to investigate CYP activities. Assays that have been developed include tolbutamide methylhydroxylase, paclitaxel 6α-hydroxylase, dextromethorphan O-demethylation, testosterone 6β-hydroxylation and coumarin 7-hydroxylase assays. These assays serve as activity markers allowing comparison of catalytic activities of mutant proteins generated. Another focus of our work is to use the developed assays as a screening tool to investigate drug-herb interactions. This was achieved by co-incubation of herbal extracts and active constituents with the probe substrates in the assays followed by characterization of the kinetic behaviors of the enzymes involved using various pharmacokinetic parameters such as Km, Vmax, IC50 and Ki. This work is currently carried out with collaboration from the Institute for Medical Research (IMR) and is supported by MOSTI’s eScienceFund under RM9. It is envisaged that this screening work will give us insights on the potential of the commonly used herbs to cause pharmacokinetic interactions with other drug substrates, and allow us to elucidate the mechanisms involved in the interactions.

Matched MeSH terms: Cytochrome P-450 CYP2C9
Role of pharmacodiagnostic of CYP2C9 variants in the optimization of warfarin therapy in Malaysia: a 6-month follow-up study

Ngow H, Teh LK, Langmia IM, Lee WL, Harun R, Ismail R, et al.

Xenobiotica, 2008 Jun;38(6):641-51.
PMID: 18570163 DOI: 10.1080/00498250801999087

1. A retrospective study was conducted to explore the importance of CYP2C9 genotyping for the initiation and maintenance therapy of warfarin in clinical practice. A total of 191 patients on warfarin therapy in a local hospital were recruited after written informed consent. Their medical records were reviewed and no intervention of warfarin dose was performed. 2. A total of 5 ml of blood were taken from each subject for DNA extraction and identification of 1, 2, 3 and 4 CYP2C9 alleles, using a nested-allele-specific-multiplex-polymerase chain reaction (PCR). Half the patients were Malays and the remaining were Chinese. 3. Two genotypes were detected; 93.2% had CYP2C9 1/1 and 6.8% were CYP2C9 1/3. Warfarin doses were higher in patients with CYP2C91/1. Patients with the 1/3 genotype experienced a higher rate of serious and life-threatening bleeding; 15.4 versus 6.2 per 100 patients per 6 months. 4. The observation clearly highlights the inadequacy of the current dosing regimens and the need to move toward a more individualized approach to warfarin therapy. Prospective clinical studies are now being conducted to assess dosing algorithms that incorporate the contribution of the genotype to allow the individualization of warfarin dose.

Matched MeSH terms: Cytochrome P-450 CYP2C9
In vitro modulatory effects on three major human cytochrome P450 enzymes by multiple active constituents and extracts of Centella asiatica

Pan Y, Abd-Rashid BA, Ismail Z, Ismail R, Mak JW, Pook PC, et al.

J Ethnopharmacol, 2010 Jul 20;130(2):275-83.
PMID: 20457244 DOI: 10.1016/j.jep.2010.05.002

ETHNOPHARMACOLOGICAL RELEVANCE: Centella asiatica (CA) has been widely cultivated as a vegetable or spice in China, Southeast Asia, India, Sri Lanka, Africa, and Oceanic countries and traditionally used for wound healing and maintaining normal blood pressure.
AIM OF THE STUDY: The present study was carried out to examine the potential modulatory effects of three commercially available active components (asiaticoside, asiatic acid and madecassic acid) and four extracts (aqueous, ethanol, dichloromethane and hexane) of CA on three major cDNA-expressed human cytochrome P450 (CYP) isoforms.
MATERIALS AND METHODS: High-performance liquid chromatography (HPLC)-based enzyme assays, namely tolbutamide 4-methyhydroxylase, dextromethorphan O-demethylase and testosterone 6beta-hydroxylase assays were developed to probe activities of CYP2C9, CYP2D6 and CYP3A4, respectively. Probe substrates were incubated with or without each active component and extract for each isoform, followed by examination of the kinetics parameters, IC(50) and K(i), to characterize modulatory effects.
RESULTS: CYP2C9 was more susceptible to inhibitory effects by CA extracts compared to CYP2D6 and CYP3A4. Moderate degree of inhibition was observed in ethanol (K(i)=39.1 microg/ml) and dichloromethane (K(i)=26.6 microg/ml) extracts implying potential risk of interaction when CYP2C9 substrates are consumed with CA products. The two extracts however showed negligible inhibition towards CYP2D6 and CYP3A4 (IC(50)'s of 123.3 microg/ml and above). Similarly CA aqueous and hexane extracts did not significantly inhibit all three isoforms investigated (IC(50)'s of 117.9 microg/ml and above). Among the active constituents investigated, asiatic acid and madecassic acid appeared to selectively inhibit CYP2C9 and CYP2D6 more than CYP3A4. Of particular interest is the potent inhibitory effect of asiatic acid on CYP2C9 (K(i)=9.1 microg/ml). This signifies potential risk of interaction when substrates for this isoform are taken together with CA products with high asiatic acid content. Inhibitions of asiatic acid with the other isoforms and that of madecassic acid with all isoforms were only moderate (K(i)'s ranged from 17.2 to 84.4 microg/ml). On the other hand, the IC(50) values for asiaticoside were high (1070.2 microg/ml or above) for all three isoforms, indicating negligible or low potential of this compound to modulate CYP enzymatic activity.
CONCLUSION: Centella asiatica extracts and active constituents inhibited CYP2C9, CYP2D6 and CYP3A4 activities with varying potency with CYP2C9 being the most susceptible isoform to inhibition. Significant inhibition was observed for asiatic acid and CA ethanol and dichloromethane extracts, implying involvement of semipolar constituents from CA in the effect. This study suggested that CA could cause drug-herb interactions through CYP2C9 inhibition.

Matched MeSH terms: Cytochrome P-450 CYP2C9
Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations

Gan GG, Phipps ME, Lee MM, Lu LS, Subramaniam RY, Bee PC, et al.

Ann Hematol, 2011 Jun;90(6):635-41.
PMID: 21110192 DOI: 10.1007/s00277-010-1119-6

Within the Asian populations, Indian patients had been reported to require higher warfarin dose compared with the Chinese and Malay patients, and this could not entirely be explained by cytochrome P450 (CYP)2C9 gene variants. Genetic variants of vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1) has been well established as one of key determinants in the different responses of warfarin amongst patients. Adult patients who attended an anticoagulation clinic with stable INR were recruited. VKORC1 and CYP2C9 genotype were sequenced, and clinical characteristics were assessed. A total of 91 Malays, 96 Chinese, and 46 Indian patients were recruited. The mean age was 55 years and 51.5% were males. The mean dose of warfarin for all patients was 3.7 mg, and the mean daily dose of warfarin was significantly higher in Indians compared with the Chinese and Malay patients, 4.9 versus 3.5 and 3.3 mg, respectively (p p CYP2C9*2 and *3 is associated with a lower maintenance dose, 2.9 versus 3.7 mg in CYP2C9*1; p CYP2C9 polymorphism contribute to the difference dose requirement amongst the patients but other additional possible factors may play a role in the Indian race.
Study site: Anticoagulation clinic, University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia

Matched MeSH terms: Cytochrome P-450 CYP2C9