Phosphodiesterase Type 5 Inhibitors: a Biochemical and Clinical Correlation Survey

International Journal of Impotence Research (2003) 15, Suppl 5, S13–S19 & 2003 Nature Publishing Group All rights reserved 0955-9930/03 $25.00 www.nature.com/ijir Phosphodiesterase type 5 inhibitors: a biochemical and clinical correlation survey NN Kim1* 1Department of Urology, Institute for Sexual Medicine, Boston University School of Medicine, Boston, Massachusetts, USA Phosphodiesterase type 5 (PDE 5) is the major cGMP hydrolyzing enzyme in penile corpus cavernosum and is an important regulator of nitric oxide-mediated smooth muscle relaxation. The critical role of PDE 5 in penile erection and the recent availability of specific and potent inhibitors of PDE 5 have enabled the development of effective oral treatment strategies that have been widely accepted by both health-care professionals and the lay public. This article examines the correlation between the available biochemical and clinical data for the PDE 5 inhibitors sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra). International Journal of Impotence Research (2003) 15, Suppl 5, S13–S19. doi:10.1038/sj.ijir.3901067 Keywords: phosphodiesterase type 5 inhibitor; sildenafil; tadalafil; vardenafil; Viagra; Cialis; Levitra; potency; efficacy; safety Introduction differing substrate specificities based upon their ability to discriminate between cGMP and adeno- sine 30,50-cyclic monophosphate (cAMP). Further- Guanosine 30,50-cyclic monophosphate (cGMP) is an more, the activity of different phosphodiesterases important mediator of smooth muscle relaxation and may be modulated by varying mechanisms. Thus, has been shown to be a key molecular regulator of regulation of cyclic nucleotide metabolism depends penile tumescence. Intracellular cGMP concentra- on the specific expression profile of the various tions are strictly controlled by the action of guanylyl phosphodiesterase types in a given tissue. Although 1–4 cyclases and cGMP-specific phosphodiesterases. several different types of phosphodiesterases have A well-defined biochemical pathway leading to been identified within penile cavernosal tissue, penile erection involves the binding of nerve- or human trabecular smooth muscle cells express endothelium-derived nitric oxide to the heme phosphodiesterase type 5 (PDE 5) as the major moiety of soluble guanylyl cyclase within the cGMP hydrolyzing enzyme.8,9 vascular smooth muscle of the resistance arteries PDE 5 was initially identified as the major cGMP 5 and the trabeculae of the corpora cavernosa. This binding protein in bovine lung and later character- activation of guanylyl cyclase by nitric oxide ized as a cGMP-binding, cGMP-specific phospho- catalyzes the formation of cGMP from GTP. Elevated diesterase.10–12 The purified protein is a homodimer levels of intracellular cGMP lead to the activation of of 99.6 kDa subunits and binds two zinc atoms per cGMP-specific phosphodiesterases which hydrolyze monomer which are necessary for catalysis.13 PDE 5 cGMP to 50-GMP. The degradation of cGMP by has two allosteric sites for cGMP binding. Occu- phosphodiesterases is one of the main mechanisms pancy of these sites is necessary for phosphorylation by which the nitric oxide signal transduction path- of PDE 5 which has been shown to occur via protein way is terminated within smooth muscle cells. kinase G-dependent mechanisms.14,15 In experi- In all, 11 main types of phosphodiesterases (some ments using recombinant bovine PDE 5, phosphor- types with multiple isoforms) have been identified ylation of the enzyme has been shown to increase 6,7 to date. Each type of phosphodiesterase has the affinity of the allosteric binding sites for cGMP and enhance catalytic activity by 50–70%.16 Recent equilibrium radioligand binding studies indicate *Correspondence: NN Kim, PhD, Department of Urology, that sildenafil binds to the catalytic site of PDE 5 with high affinity (0.83–12 nM) and limited capacity Boston University School of Medicine, 700 Albany St. 17 W607, Boston, MA 02118, USA. (0.6 mol/mol-subunit). The presence of up to 3 E-mail: [email protected] 10 mM of cGMP enhanced the affinity of [ H]silde- PDE 5 — a survey NN Kim S14 nafil for PDE 5, most likely through interactions at the allosteric binding sites. These data suggest that sildenafil may potentiate its own action by inhibit- ing PDE 5 and causing the elevation of intracellular cGMP levels, which further increases the affinity of sildenafil for PDE 5. Whether this phenomenon is specific for sildenafil or present as a general mechanism of potentiation for any PDE 5 inhibitor remains to be seen. The critical role of PDE 5 in penile erectile physiology and the synthesis and identification of specific and potent inhibitors of PDE 5 have enabled the development of effective oral treatment strategies that have been widely accepted by both health- care professionals and the lay public. This brief review will examine the correlation between the available biochemical and clinical data for the PDE 5 inhibitors sildenafil (Viagra), vardenafil (Levitra) and tadalafil (Cialis) (see Figure 1 for chemical Figure 1 Chemical structures of sildenafil, tadalafil and varde- structures). nafil. Potency and efficacy of PDE 5 inhibitors inversely proportional to the concentration of drug required to inhibit an enzyme (eg the lower the IC50 or Ki, the greater the potency). The potency and efficacy of any therapeutic agent is As can be seen in Figure 2, the ranking of IC50 dependent upon numerous factors. For orally ad- values was identical in two different studies utiliz- ministered PDE 5 inhibitors, these factors include: ing purified PDE 5 preparations. Vardenafil was (1) dissolution and absorption time (tmax), (2) found to be the most potent, followed by sildenafil solubility and plasma protein associations, (3) tissue and tadalafil.18,19 (E Gbekor, personal communica- and cell permeability, (4) binding and dissociation tion, 2002) Similar differences in inhibitory potency rates of inhibitors to PDE 5 (Kd,IC50 and Ki), and (5) were observed in comparing sildenafil and varde- metabolism and clearance (t1/2). Any of these factors nafil incubated with human cavernosal tissue can significantly influence clinical measures of extracts.20 These differences in potency between potency and efficacy in patients and may lead to sildenafil and vardenafil were maintained in func- inconsistencies between clinical and laboratory tional assays that measured cGMP accumulation in data. In laboratory studies, parameters of affinity cultured smooth muscle cells and erectile function and enzyme inhibitory capacity are the most in both anesthetized and conscious rabbits.20–22 common means of comparing drug potency. For With the exception of IC50 determinations, direct the purposes of this discussion, the pharmacological head-to-head comparative studies for all three PDE 5 definition of potency will be employed. Potency is inhibitors have not been reported. However, the 18 19 Figure 2 Comparison of IC50 values for PDE 5 inhibitors. See Saenz et al, Gresser and Gleiter and E Gbekor, personal communication. International Journal of Impotence Research PDE 5 — a survey NN Kim S15 Table 1 Pharmacokinetic parameters for PDE 5 inhibitors dicated varying extents of enhancement in erectile function, all have reported significant increases in Parameter Sildenafil Tadalafil Vardenafil the percentage of successful intercourse attempts (100 mg) (20 mg) (20 mg) and the percentage of patients who responded ‘yes’ to the global assessment question (GAQ), ‘Did your t (h) 1.2 2.0 0.7 max treatment improve your erections?’. Increasingly, t1/2 (h) 3.8 17.5 3.9 Cmax (ng/ml) 327.0 378.0 20.9 studies using sildenafil have recruited patients who are considered difficult to treat for erectile dysfunc- See Corbin and Francis23 and Porst24 tion. Limited, but encouraging data indicate that Viagra significantly enhances erectile function in patients with the following conditions: diabetes mellitus, multiple sclerosis, renal failure/kidney available preclinical in vitro and in vivo data suggest dialysis, organ (heart, kidney) transplant, stable that vardenafil is a more potent inhibitor of PDE 5 cardiovascular disease with no nitrate therapy, than either sildenafil or tadalafil. Additional differ- previous use of intracavernosal injection therapy, ences between the three PDE 5 inhibitors can be SSRI therapy for depression, nerve-sparing radical seen from the pharmacokinetic data (Table 1).23,24 prostatectomy, Parkinson’s disease, spina bifida, or While the dose for sildenafil was five times higher spinal cord injury with at least partial response to than either tadalafil or vardenafil, the most notable penile vibratory stimulation.27–29 distinctions are the longer half-life (t1/2) of tadalafil While the clinical data for vardenafil and tadalafil and the lower maximal plasma concentration (Cmax) are not as extensive as sildenafil, similar outcome of vardenafil. It is likely that the prolonged half-life measures indicate that both PDE 5 inhibitors are of tadalafil results in its accumulation and leads to a effective in treating men diagnosed with erectile higher plasma concentration than vardenafil dysfunction.24,30–34 Separate studies indicate that although equal doses of each inhibitor were admi- vardenafil significantly improves erectile function nistered. in men with type I or type II diabetes mellitus and The time of onset of action for each PDE 5 also in men with a history of radical prostatect- inhibitor is not readily available. However, in a omy.35 In a recently published phase 3,

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