Involvement of CYP3A in the Metabolism of Eplerenone in Humans and Dogs: Differential Metabolism by CYP3A4 and CYP3A5

Cook, Chyung S.; Berry, Loren; Kim, David H.; Burton, Earl G.; Hribar, Jeremy D.; Zhang, Liming

doi:10.1124/dmd.30.12.1344

Cited by 59 publications

(32 citation statements)

References 17 publications

(16 reference statements)

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“…The primary route of elimination for eplerenone is through CYP 450 3A4-mediated metabolism [20]. The apparent plasma clearance of eplerenone is ≈10L/hr and its elimination half-life is 4 to 6-hrs.…”

Section: Eplerenonementioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Mineralocorticoid Blocking Agents and their Effects on Potassium Homeostasis

2005

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Spironolacotone and eplerenone are mineralocorticoid-blocking agents used for their ability to block both the epithelial and non-epithelial actions of aldosterone. Spironolactone is a non-selective mineralocorticoid receptor antagonist with moderate affinity for both progesterone and androgen receptors. The latter property increases the likelihood of endocrine side effects with spironolactone including loss of libido, menstrual irregularities, gynecomastia and impotence. Eplerenone is a next generation aldosterone receptor antagonist selective for aldosterone receptors alone. This lesser affinity for progesterone and androgen receptors was arrived at by replacing the 17-alpha -thioacetyl group of spironolactone with a carbomethoxy group. Eplerenone is further distinguished from spironolactone by its shorter half-life and the fact that it does not have any active metabolites. Both eplerenone and spironolactone are effective antihypertensive agents and each has been shown to improve the morbidity and mortality of heart failure. Eplerenone or spironolactone use can increase serum potassium values and occasionally results in clinically relevant hyperkalemia. This is more apt to occur with spironolactone due to the very long half-life of several of its active metabolites.

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Section: Eplerenonementioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Mineralocorticoid Blocking Agents and their Effects on Potassium Homeostasis

2005

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“…Recently, however, CYP3A5 is reported to be more abundant than CYP3A4 in the lung and kidney (Ding and Kaminsky, 2003). CYP3A4-specific probe substrates and/or inactivators have been identified (Cook et al, 2002;Khan et al, 2002), but specific probe substrates for CYP3A5 have not yet been reported. CYP3A7 is the major fetal form and is rarely expressed in adults.…”

Section: Introductionmentioning

confidence: 99%

Differential Enantioselectivity and Product-Dependent Activation and Inhibition in Metabolism of Verapamil by Human Cyp3as

Shen¹,

Fitzloff²,

Cook³

2004

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:In vitro studies of enantioselective metabolism of R-(؉)-and S-(؊)-verapamil (VER) were conducted using human cDNA-expressed CYP3A isoforms, CYP3A4, CYP3A5, and CYP3A7. N-dealkylated products nor-VER [2,8-bis-(3,4-dimethoxyphenyl)-2-isopropyl-6-azaoctanitrile] and D617 [2-(3,4-dimethoxyphenyl)-5-methylamino-2-isopropylvaleronitrile] were the major metabolites for all CYP3A isoforms regardless of enantiomer. Enantioselectivity of CYP3A4 and CYP3A7 was most similar among the three isoforms. This coincides with the degree of homology of amino acids at the active sites and in the total amino acid sequences of the enzymes. Biphasic substrate inhibition was observed for the formation of nor-VER and D617, whereas simple biphasic kinetics were observed for the formation of O-demethylated products for both enantiomers with CYP3A4. The biphasic substrate inhibition was observed only for nor-VER, and simple biphasic kinetics were observed for D617and O-demethylated products for both enantiomers with CYP3A5. However, with CYP3A7, D617 and O-demethylated products showed typical Michaelis-Menten kinetics, and only nor-VER displayed substrate (monophasic) inhibition. When metabolic rates of VER were determined in the presence of three different effectors, midazolam, testosterone, and nifedipine, activation, inhibition, or activation and inhibition of VER metabolism was observed depending on the enantiomers, metabolites, effectors, and cytochrome P450 isoforms. Addition of anti-CYP3A4 antibody inhibited formation of all metabolites for both CYP3A4 and CYP3A5. The atypical phenomena (biphasic substrate inhibition, activation, and inhibition depending on product formation) of VER kinetics could be adequately explained by introducing the concept of steric interaction into a two binding-site model.Cytochrome P450 (P450 1 ) 3A is the most important human P450 subfamily due to its high relative abundance in the liver and its broad substrate specificity (Thummel and Wilkinson, 1998). The enzymes within this subfamily are estimated to participate in the metabolism of approximately 50% of marketed drugs known to undergo oxidative metabolism (Benet, 1996) and are responsible for many metabolismbased drug-drug interactions. Four members of the CYP3A subfamily have been reported in humans: CYP3A4, CYP3A5, CYP3A7 (Nelson et al., 1996), and CYP3A43 (Domanski et al., 2001a). CYP3A4 is the most abundant hepatic and intestinal form. CYP3A5 is the second most abundant CYP3A in adult human liver and shows reduced metabolic capability compared with CYP3A4 in most cases. Recently, however, CYP3A5 is reported to be more abundant than CYP3A4 in the lung and kidney (Ding and Kaminsky, 2003). CYP3A4-specific probe substrates and/or inactivators have been identified (Cook et al., 2002;Khan et al., 2002), but specific probe substrates for CYP3A5 have not yet been reported. CYP3A7 is the major fetal form and is rarely expressed in adults. Comparative in vitro metabolic activities ...

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“…There are 84% amino acid sequence similarity and overlapping substrate specificities between CYP3A4 and CYP3A5 (Aoyama et al, 1989;Wrighton and Stevens, 1992). However, some differences have been reported in enzymatic properties of CYP3A4 and CYP3A5, including substrate specificity and inhibition (Gibbs et al, 1999;Cook et al, 2002;Patki et al, 2003;Emoto and Iwasaki, 2006). Unlike CYP3A4, CYP3A5 is polymorphically expressed in human liver (Koch et al, 2002;Xie et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The Contributions of Cytochromes P450 3A4 and 3A5 to the Metabolism of the Phosphodiesterase Type 5 Inhibitors Sildenafil, Udenafil, and Vardenafil

Ku¹,

Ahn²,

Seo³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The role of the genetically polymorphic CYP3A5 in the metabolism of CYP3A substrates is unclear. We investigated the contributions of the CYP3A4 and CYP3A5 isoforms to the metabolism of the phosphodiesterase type 5 inhibitors (PDE5Is) sildenafil, udenafil, and vardenafil. In vitro incubation studies of sildenafil N-demethylation, udenafil N-dealkylation, and vardenafil N-deethylation were conducted using recombinant CYP3A enzymes and 15 human liver microsome (HLM) preparations with predetermined CYP3A5 genotypes. Recombinant CYP3A4 and CYP3A5 both produced N-desalkyl metabolites of sildenafil, udenafil, and vardenafil. The catalytic efficiency (Cl int ‫؍‬ V max /apparent K m ) of the rCYP3A5 isoform for vardenafil N-deethylation was about 3.2-fold that of rCYP3A4, whereas the intrinsic clearance rates for N-dealkylation of both sildenafil and udenafil were similar between rCYP3A5 and rCYP3A4. The metabolite formation activity was higher in HLMs heterozygous for the CYP3A5*3 allele (n ‫؍‬ 9) than in HLMs homozygous for CYP3A5*3 (n ‫؍‬ 6). These findings suggest that CYP3A5 and CYP3A4 play a significant role in the metabolism of PDE5Is. The genetic polymorphism of CYP3A5 may contribute to interindividual variability in the disposition of PDE5Is, especially vardenafil. Further in vivo studies are needed to confirm the effects of CYP3A5 genotypes on the pharmacokinetics of PDE5Is.Sildenafil, udenafil, and vardenafil are potent, selective inhibitors of cyclic GMP-specific phosphodiesterase type 5 (PDE5) in the smooth muscle cells lining blood vessels, especially in the corpus cavernosum of the penis. These drugs are used for effective p.o. treatment of erectile dysfunction. Previous studies have reported large interindividual variability in the pharmacokinetic disposition of sildenafil, udenafil, and vardenafil (Klotz et al., 2001;Rajagopalan et al., 2003;Shim et al., 2003;Bischoff, 2004;Gupta et al., 2005;Mehrotra et al., 2007). Vardenafil showed the highest interindividual variation among three PDE5 inhibitors (PDE5Is), with a 14-fold variability among subjects receiving 20 mg of vardenafil (Klotz et al., 2001;Rajagopalan et al., 2003). The mechanisms of these large interindividual variations in vivo have not been elucidated.Sildenafil, udenafil, and vardenafil undergo N-dealkylation in the liver and intestine, and cytochrome P450 (P450) 3A is primarily involved in their metabolism (Fig. 1) (Ji et al., 2004; Kivisto et al., 2004;Mehrotra et al., 2007). CYP3A is most abundant human hepatic P450 and is involved in the metabolism of approximately 50% of commonly administered drugs (Evans and Relling, 1999). In adults, CYP3A4 and CYP3A5 are predominant among the four known isoforms (CYP3A4, CYP3A5, CYP3A7, and CYP3A43) in the liver and intestine (Nelson et al., 1996). CYP3A5 is similar to CYP3A4 with regard to sequence and substrate selectivity (Kuehl et al., 2001). There are 84% amino acid sequence similarity and overlapping substrate specificities between CYP3A4 and CYP3A5 (Aoyama et al., 1989;Wrighton and ...

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Involvement of CYP3A in the Metabolism of Eplerenone in Humans and Dogs: Differential Metabolism by CYP3A4 and CYP3A5

Cited by 59 publications

References 17 publications

Pharmacokinetics and Pharmacodynamics of Mineralocorticoid Blocking Agents and their Effects on Potassium Homeostasis

Pharmacokinetics and Pharmacodynamics of Mineralocorticoid Blocking Agents and their Effects on Potassium Homeostasis

Differential Enantioselectivity and Product-Dependent Activation and Inhibition in Metabolism of Verapamil by Human Cyp3as

The Contributions of Cytochromes P450 3A4 and 3A5 to the Metabolism of the Phosphodiesterase Type 5 Inhibitors Sildenafil, Udenafil, and Vardenafil

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