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

Abstract

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 ...

Preparation of human drug metabolites using fungal peroxygenases

“…propranolol to 5-hydroxypropranolol (CYP2D6) [29], tolbutamide to 4-hydroxytolbutamide (CYP2C9) [30], naproxen to O-desmethylnaproxen (CYP1A2) [31], acetanilide to acetaminophen (CYP1A2) [31,32] and sildenafil to N-desmethylsildenafil (CYP3A4) [33].…”

Contribution of CYP3A Isoforms to Dealkylation of PDE5 Inhibitors: A Comparison between Sildenafil N-Demethylation and Tadalafil Demethylenation

“…11) They also demonstrated that the mean rate for N-desalkyl metabolite formation from sildenafil was high in human liver microsome preparations with CYP3A5 activity (heterozygous for CYP3A5*1/*3 alleles) compared to those with null CYP3A5 activity (homozygous for CYP3A5*3 allele). 11) These results suggested that genetic polymorphism of CYP3A5 at least partly contributes to interindividual variability in the disposition of sildenafil. On the other hand, tadalafil is eliminated predominantly by oxidative metabolism to a catechol via demethylenation ( Fig.…”

“…1). Recently, Ku et al 11) showed that both CYP3A4 and CYP3A5 played a significant role in the metabolism of sildenafil using CYP3A supersomes. That is, the intrinsic clearance for N-dealkylation of sildenafil by CYP3A5 and CYP3A4 were 0.09 and 0.07 µL/ min/pmol P450, respectively.…”

Inhibitory Effects of Gastrointestinal Drugs on CYP Activities in Human Liver Microsomes

“…CYP3A4 is responsible for the metabolism of more than 50% of therapeutic drugs 15) such as nifedipine, 16,17) triazolam, 18) simvastatine, [19][20][21] and vardenafil. 22) Because of the pharmacological properties of gastrointestinal drugs, it is often used concomitantly with other therapeutic agents. Therefore, careful attention is needed to avoid drug interactions through CYP3A4 inhibition.…”