Recent animal studies highlighted a possible interaction between chronic PDE5 inhibition and glucose homeostasis which occurs through a marked improvement of high fat diet induced insulin resistance. Although data defining the magnitude of potential interactions with the PDE5 agents are quite limited, some general observations can be made. Yet, differences in inhibitor dose and lack of study details make comparisons more difficult.

Erythromycin also appears to produce a larger effect on vardenafil than on Fildena. These differences between Fildena and vardenafil again may be partially explained by differences in first-pass metabolism. The effect of ritonavir on Fildena’s Cmax and AUC is less than that of a similar dose of ritonavir on vardenafil’s parameters.

The effect of ketoconazole on vardenafil appears to be greater than its effect on Fildena. Using what interaction data are available and the known properties of the object drugs can be helpful in assessing unreported, potential interactions. Moreover, the PDE5 drugs differ in some of their pharmacokinetic parameters.

In addition, Fildena and perhaps vardenafil are metabolized by CYP2C9, although to a minor extent.4 Furthermore, vardenafil metabolism has been reported to be mediated by CYP3A5, an enzyme closely related to CYP3A4. Although published data are limited, the PDE5 agents all appear to be primarily metabolized by cytochrome P-450 3A4. The PDE5 compounds also are susceptible to pharmacokinetic interactions caused by drugs that induce or inhibit their metabolism.

Specific cGMP binding by the cGMP binding domains of cGMP-binding cGMP specific phosphodiesterase. Substrate-and-kinase-directed regulation of phosphorylation of a cGMP-binding phosphodiesterase by cGMP. Expression of different phosphodiesterase genes in human cavernous smooth muscle.

However, important questions about the properties and function of PDE inhibitors still need to be answered. Increased degradation occurs simply by mass action effect (ie, increased substrate availability for PDE5.) Also, PKG phosphorylates PDE5, causing its activation. Each PDE5 inhibitor is thought to exhibit the same mechanism, but this has not been established.

16 , 17 This represents negative feedback control in smooth muscle cells, since elevation of cGMP stimulates cGMP degradation. Messenger RNA has been detected in human corpus cavernosum tissue for the human PDE isoforms—_PDE1A, PDE1B, PDE1C, PDE2A, PDE3A, PDE4A, PDE4B, PDE4C, PDE4D, PDE5A, PDE7A, PDE8A, and PDE9A. PDE11, for example, degrades both cAMP and cGMP, whereas PDE4 is specific for cAMP, and PDE5 is specific for cGMP.

PDE5 is the predominant phosphodiesterase in the corpus cavernosum. Cyclic GMP activates cGMP-dependent protein kinase (PKG), which in turn phosphorylates several proteins. This article will review the biochemical pathways involved in erection, the role of PDE5 in these pathways, and the molecular mechanisms involved in PDE activity.
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