Tadalafil liquid shows up in a lot of lab requests, and most of what’s written about it online is either marketing or recycled patient leaflets. We wanted something better. So this is a plain look at what the research shows about tadalafil itself: how it was found, what it blocks, how long it lingers, and what the published work on liquid preparations actually measured. Every number below comes from a paper we read and linked.
Key findings
- Tadalafil inhibits PDE5 with an IC50 of 5 nM and came out of a series where only the cis-(6R,12aR) form was strongly active (Daugan 2003).
- It’s about 1,000-fold selective for PDE5 over PDE6, versus roughly 12-fold for sildenafil (Huang 2013).
- Against PDE11A4, its selectivity is the narrowest of the three classic PDE5 inhibitors, about 40-fold (Weeks 2005).
- Mean half-life in 237 healthy volunteers was 17.5 hours, and food barely changed exposure (Forgue 2006).
- A 5 mg/mL oral suspension kept at least 99% of its starting concentration for 91 days at room temperature (Pettit 2012).
How tadalafil was found
Tadalafil didn’t come from tweaking sildenafil. It came out of a separate French research program built on a fused indole ring system. In the second of two 2003 discovery papers, Daugan’s team swapped a hydantoin ring for a piperazinedione, added a 3,4-methylenedioxyphenyl group, and landed on compound 12a, later named tadalafil [1].
Stereochemistry turned out to be everything. Of the possible isomers, the cis-(6R,12aR) one was by far the strongest PDE5 inhibitor. That’s the molecule you’re working with today, C22H19N3O4, molecular weight about 389.4.
The same paper reported a 5 nM IC50 against PDE5 and a drop in blood pressure of 30 mmHg lasting more than 7 hours in spontaneously hypertensive rats. That long tail would turn out to be the compound’s signature.
What PDE5 inhibition does
Here’s the short version. Nitric oxide switches on soluble guanylyl cyclase, which makes cGMP. cGMP relaxes smooth muscle. PDE5 breaks cGMP down. Block PDE5 and cGMP hangs around longer, so the relaxation signal is stronger and lasts longer.
That’s why the Galiè group framed tadalafil as acting on “the final mediator in the nitric oxide pathway” in their pulmonary work [2]. Note what it doesn’t do. Tadalafil doesn’t make nitric oxide. If there’s no upstream NO signal in your model, there’s little cGMP to protect, and you’ll see little effect. Worth remembering when an experiment looks flat.
Selectivity across the PDE family
There are several PDE families, and a few of them look a lot like PDE5. Two matter most for interpreting data.
PDE6 sits in the retina. Huang and colleagues pulled together bioassay values of 5 nM for PDE5 and 5,100 nM for PDE6 with tadalafil, against 6 and 74 nM for sildenafil [3]. Their modeling pinned much of the difference on two residues in the binding pocket (Val782 and Leu804 in PDE5, Val738 and Met760 in PDE6).
PDE11 is the weaker spot. Weeks and colleagues purified human PDE11A4 and compared it head to head with PDE5 [4]. Tadalafil favored PDE5 by about 40-fold, compared with 9,300-fold for vardenafil and 1,000-fold for sildenafil. The authors still judged cross-reaction unlikely at typical exposures. If your system expresses a lot of PDE11, though, keep it in mind.
| Compound | PDE5 vs PDE6 | PDE5 vs PDE11A4 |
|---|---|---|
| Tadalafil | about 1,000-fold | about 40-fold |
| Sildenafil | about 12-fold | about 1,000-fold |
| Vardenafil | not in these papers | about 9,300-fold |
For a side-by-side with the older compound, see our sildenafil compound page.
Pharmacokinetics: why it lasts
The best single dataset is Forgue’s 2006 pooled analysis of 13 clinical pharmacology studies covering 237 healthy volunteers [5]. Peak plasma levels came at about 2 hours. After that, concentrations fell almost monoexponentially with a mean half-life of 17.5 hours (5th to 95th percentile, 11.5 to 29.6). Apparent clearance was low, 2.48 L/h, and apparent volume of distribution was 62.6 L.
A few other results are handy if you’re designing a study. Exposure scaled linearly. Food had negligible effect. Time of day didn’t matter much. With repeated daily exposure, steady state arrived by day 5, with about 1.6-fold accumulation, which is just what that half-life predicts. Body mass, age, sex and smoking status made no meaningful difference.
Pulmonary vascular research
Tadalafil’s best-studied area is pulmonary arterial hypertension. The PHIRST trial randomized 405 patients to placebo or one of four once-daily levels for 16 weeks [2]. Six-minute walk distance rose in step with the level given, though only the top level hit the prespecified significance cutoff, with a placebo-corrected gain of 33 m. The FDA approved tadalafil for PAH in 2009, as Arif and Poon summarized in their review [6].
We’re reporting that as context for the pharmacology. It’s not a suggestion about use.
What “liquid” means in the literature
Tadalafil is poorly soluble in water, which is the real reason liquid preparations need care. Hamishehkar’s group screened common solvents and found it dissolved best in N-methyl pyrrolidone, compared with ethanol, glycerin, PEG 400 and propylene glycol [7]. Their twist: higher solubility in a vehicle generally meant slower permeation through rat skin. Solvency and delivery pulled in opposite directions.
The most useful stability paper is Pettit’s [8]. They made a 5 mg/mL suspension in a 1:1 mix of two commercial suspending and sweetening vehicles, stored it in amber plastic bottles at 23 to 25 °C, and assayed it by stability-indicating HPLC. At least 99% of the starting tadalafil remained at 91 days, with no change in color, odor, taste or pH and no visible microbial growth.
So a liquid form can be stable, but that result belongs to that vehicle, that container and that temperature. Change any of them and you should verify again. We’d also suggest confirming concentration by HPLC before a study starts rather than trusting a label. Our tadalafil compound page lists the basic chemistry.
Older versions of this page talked about “tadalafil citrate.” We couldn’t find primary literature on a citrate salt of tadalafil, so we’ve dropped it. The published work is on tadalafil base.
References
- Daugan A, Grondin P, Ruault C, et al. The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione analogues. J Med Chem. 2003. PMID 14521415
- Galiè N, Brundage BH, Ghofrani HA, et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009. PMID 19470885
- Huang YY, Li Z, Cai YH, et al. The molecular basis for the selectivity of tadalafil toward phosphodiesterase 5 and 6: a modeling study. J Chem Inf Model. 2013. PMID 24180640
- Weeks JL, Zoraghi R, Beasley A, et al. High biochemical selectivity of tadalafil, sildenafil and vardenafil for human phosphodiesterase 5A1 (PDE5) over PDE11A4 suggests the absence of PDE11A4 cross-reaction in patients. Int J Impot Res. 2005. PMID 15538396
- Forgue ST, Patterson BE, Bedding AW, et al. Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol. 2006. PMID 16487221
- Arif SA, Poon H. Tadalafil: a long-acting phosphodiesterase-5 inhibitor for the treatment of pulmonary arterial hypertension. Clin Ther. 2011. PMID 21762988
- Hamishehkar H, Khoshbakht M, Jouyban A, Ghanbarzadeh S. The relationship between solubility and transdermal absorption of tadalafil. Adv Pharm Bull. 2015. PMID 26504764
- Pettit RS, Johnson CE, Caruthers RL. Stability of an extemporaneously prepared tadalafil suspension. Am J Health Syst Pharm. 2012. PMID 22441791
Disclaimer: This content is intended for research purposes only and is not meant to constitute medical advice.
This educational material discusses laboratory research concepts only. Loti Labs products are intended strictly for research and development use and are not for human consumption.
