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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 determination of the effect of Andrographis paniculata extracts and andrographolide on human hepatic cytochrome P450 activities

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

J Nat Med, 2011 Jul;65(3-4):440-7.
PMID: 21365364 DOI: 10.1007/s11418-011-0516-z

We investigated the effects of Andrographis paniculata (AP) extracts and andrographolide on the catalytic activity of three human cDNA-expressed cytochrome P450 enzymes: CYP2C9, CYP2D6 and CYP3A4. In vitro probe-based high performance liquid chromatography assays were developed to determine CYP2C9-dependent tolbutamide methylhydroxylation, CYP2D6-dependent dextromethorphan O-demethylation and CYP3A4-dependent testosterone 6β-hydroxylation activities in the presence and absence of AP extracts and andrographolide. Our results indicate that AP ethanol and methanol extracts inhibited CYP activities more potently than aqueous and hexane extracts across the three isoforms. Potent inhibitory effects were observed on CYP3A4 and CYP2C9 activities (K (i) values below 20 μg/ml). Andrographolide was found to exclusively but weakly inhibit CYP3A4 activity. In conclusion, data presented in this study suggest that AP extracts have the potential to inhibit CYP isoforms in vitro. There was, however, variation in the potency of inhibition depending on the extracts and the isoforms investigated.

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
Clinical relevance of VKORC1 (G-1639A and C1173T) and CYP2C9*3 among patients on warfarin

Teh LK, Langmia IM, Fazleen Haslinda MH, Ngow HA, Roziah MJ, Harun R, et al.

J Clin Pharm Ther, 2012 Apr;37(2):232-6.
PMID: 21507031 DOI: 10.1111/j.1365-2710.2011.01262.x

Testing for cytochrome P450-2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles is recommended by the FDA for dosing of warfarin. However, dose prediction models derived from data obtained in one population may not be applicable to another. We therefore studied the impact of genetic polymorphisms of CYP2C9 and VKORC1 on warfarin dose requirement in Malaysia.

Matched MeSH terms: Cytochrome P-450 CYP2C9
Effect of eurycomanone on cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 in vitro

Pan Y, Tiong KH, Abd-Rashid BA, Ismail Z, Ismail R, Mak JW, et al.

J Nat Med, 2014 Apr;68(2):402-6.
PMID: 23881640 DOI: 10.1007/s11418-013-0794-8

Eurycomanone, an active constituent isolated from Eurycoma longifolia Jack, was examined for modulatory effects on cytochrome P450 (CYP) isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 using in vitro assays. The IC50 value was determined to assess the potencies of modulation for each CYP isoform. Our results indicated that eurycomanone did not potently inhibit any of the CYP isoforms investigated, with IC50 values greater than 250 μg/ml. Hence there appears to be little likelihood of drug-herb interaction between eurycomanone or herbal products with high content of this compound and CYP drug substrates via CYP inhibition.

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