Contribution of cytochrome P450 3A4 and 3A5 to the metabolism of atorvastatin

Park, J.-E.; Kim, K.-B.; Bae, Soo Kyung; Moon, Byoung Seok; Liu, K.-H.; Shin, Jae‐Gook

doi:10.1080/00498250802334391

Cited by 90 publications

(45 citation statements)

References 18 publications

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“…An interesting finding was that atorvastatin ortho-hydroxylation showed a high selectivity for recombinantly expressed CYP3A4 compared with CYP3A5, with up to 16-fold activity difference, depending on the conditions. This finding is in contrast to the study by Jacobsen et al (2000), who observed similar activities for the two isoforms, whereas Park et al (2008) also reported higher intrinsic clearance of CYP3A4 compared with that of CYP3A5 for ortho-and para-hydroxylation (5-and 2.4-fold, respectively). The selectivity difference was further supported by our liver microsome data, for which the correlation between atorvastatin ortho-hydroxylation and CYP3A4 was much higher compared with that with CYP3A5 (r s ϭ 0.78, versus 0.37, respectively; p Ͻ 0.0001).…”

Section: Discussioncontrasting

confidence: 99%

Profiling Induction of Cytochrome P450 Enzyme Activity by Statins Using a New Liquid Chromatography-Tandem Mass Spectrometry Cocktail Assay in Human Hepatocytes

Feidt¹,

Klein²,

Hofmann³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Human hepatocytes in primary culture are a very useful model to directly assess induction of gene expression by xenobiotics. We developed a cytochrome P450 (P450) activity cocktail assay using model substrates for the seven important P450s 1A2 (phenacetin), 2B6 (bupropion), 2C8 (amodiaquine), 2C9 (tolbutamide), 2C19 (Smephenytoin), 2D6 (propafenone), and 3A4 (atorvastatin). Metabolite formation was determined by liquid chromatography-tandem mass spectrometry in hepatocyte culture supernatants. Atorvastatin has not been previously assessed as a CYP3A probe drug. We demonstrate highly selective atorvastatin ortho-hydroxylation by CYP3A4 by recombinant P450s. In human liver microsomes orthohydroxyatorvastatin formation was highly correlated with CYP3A4 protein content (r s ‫؍‬ 0.78, p < 0.0001, n ‫؍‬ 150). We profiled induction of these P450 activities in primary human hepatocytes after treatment with 30 M atorvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin for 24 to 72 h. Except for pravastatin, all statins induced P450 activities to various degrees, approximately in the order atorvastatin > simvastatin > lovastatin > rosuvastatin. Inducibility of P450s followed the order CYP2C8 > CYP3A4 > CYP2C9 > CYP2B6 > CYP2C19 ϳ CYP2D6 > CYP1A2. The strongest induction was observed for amodiaquine N-desalkylation, which was induced approximately 20-fold. Quantitative reverse transcription-polymerase chain reaction confirmed corresponding changes on the mRNA level with even more dramatic induction up to almost 100-fold. These data suggest a broader inducing effect of statins on cytochrome P450s and possibly other absorption, distribution, metabolism, and excretion genes than previously known, thus further emphasizing their drug-drug interaction potential. Our cocktail assay should be helpful for economical use of human hepatocytes in the assessment of P450 induction by drugs and drug candidates.

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Section: Discussioncontrasting

confidence: 99%

Profiling Induction of Cytochrome P450 Enzyme Activity by Statins Using a New Liquid Chromatography-Tandem Mass Spectrometry Cocktail Assay in Human Hepatocytes

Feidt¹,

Klein²,

Hofmann³

et al. 2010

Drug Metab Dispos

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“…As for substrates for which the clinical significance of CYP3A4*16 has not been evaluated, this study demonstrated that ATV metabolism was markedly affected by CYP3A4.16. Because CYP3A4 (but not CYP3A5) is the major enzyme involved in the formation of the two ATV metabolites: 2-and 4-OH-ATV (Park et al, 2008), the clinical relevance of CYP3A4*16 for efficacy and/or adverse reactions of ATV should be further investigated. In contrast, CYP3A4.16 retained its catalytic activity toward DTX, and thus it is predicted that this allele does not substantially influence the metabolism of DTX in vivo.…”

Section: Resultsmentioning

confidence: 99%

*CYP3A4**16andCYP3A4*18Alleles Found in East Asians Exhibit Differential Catalytic Activities for Seven CYP3A4 Substrate Drugs

Maekawa

Harakawa²,

Yoshimura³

et al. 2010

Drug Metab Dispos

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ABSTRACT:CYP3A4, the major form of cytochrome P450 (P450) expressed in the adult human liver, is involved in the metabolism of approximately 50% of commonly prescribed drugs. Several genetic polymorphisms in CYP3A4 are known to affect its catalytic activity and to contribute in part to interindividual differences in the pharmacokinetics and pharmacodynamics of CYP3A4 substrate drugs. In this study, catalytic activities of the two alleles found in East Asians, CYP3A4*16 (T185S) and CYP3A4*18 (L293P), were assessed using the following seven substrates: midazolam, carbamazepine, atorvastatin, paclitaxel, docetaxel, irinotecan, and terfenadine. The holoprotein levels of CYP3A4.16 and CYP3A4.18 were significantly higher and lower, respectively, than that of CYP3A4.1 when expressed in Sf21 insect cell microsomes together with human NADPH-P450 reductase. CYP3A4.16 exhibited intrinsic clearances (V max /K m ) that were lowered considerably (by 84-60%) for metabolism of midazolam, carbamazepine, atorvastatin, paclitaxel, and irinotecan compared with CYP3A4.1 due to increased K m with or without decreased V max values, whereas no apparent decrease in intrinsic clearance was observed for docetaxel. On the other hand, K m values for CYP3A4.18 were comparable to those for CYP3A4.1 for all substrates except terfenadine; but V max values were lower for midazolam, paclitaxel, docetaxel, and irinotecan, resulting in partially reduced intrinsic clearance values (by 34-52%). These results demonstrated that the impacts of both alleles on CYP3A4 catalytic activities depend on the substrates used. Thus, to evaluate the influences of both alleles on the pharmacokinetics of CYP3A4-metabolized drugs and their drug-drug interactions, substrate drug-dependent characteristics should be considered for each drug.

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“…For instance, gain or loss of catalytic function in the CYP2C8 gene causes an alteration of cerivastatin metabolic clearance of up to six-fold compared with the wild-type enzyme, altering cerivastatin pharmacokinetics and influencing, at least in part, the susceptibility to the development of myotoxicity (Kaspera et al, 2010). Conversely, a recently discovered polymorphism of CYP3A5 gene seems not to be an important factor in the modification of atorvastatin disposition and pharmacodynamics in humans (Park et al, 2008).…”

Section: Statins and Cancer: Pros And Consmentioning

confidence: 99%

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

Gazzerro

Proto²,

Gangemi³

et al. 2011

Pharmacol Rev

390

370

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Contribution of cytochrome P450 3A4 and 3A5 to the metabolism of atorvastatin

Cited by 90 publications

References 18 publications

Profiling Induction of Cytochrome P450 Enzyme Activity by Statins Using a New Liquid Chromatography-Tandem Mass Spectrometry Cocktail Assay in Human Hepatocytes

Profiling Induction of Cytochrome P450 Enzyme Activity by Statins Using a New Liquid Chromatography-Tandem Mass Spectrometry Cocktail Assay in Human Hepatocytes

*CYP3A4**16andCYP3A4*18Alleles Found in East Asians Exhibit Differential Catalytic Activities for Seven CYP3A4 Substrate Drugs

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

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Contribution of cytochrome P450 3A4 and 3A5 to the metabolism of atorvastatin

Cited by 90 publications

References 18 publications

Profiling Induction of Cytochrome P450 Enzyme Activity by Statins Using a New Liquid Chromatography-Tandem Mass Spectrometry Cocktail Assay in Human Hepatocytes

Profiling Induction of Cytochrome P450 Enzyme Activity by Statins Using a New Liquid Chromatography-Tandem Mass Spectrometry Cocktail Assay in Human Hepatocytes

CYP3A4*16andCYP3A4*18Alleles Found in East Asians Exhibit Differential Catalytic Activities for Seven CYP3A4 Substrate Drugs

Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer

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Product

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*CYP3A4**16andCYP3A4*18Alleles Found in East Asians Exhibit Differential Catalytic Activities for Seven CYP3A4 Substrate Drugs