Pharmacological properties of diprophylline and its potential role in COVID-19

Introduction

Diprophylline (also known as dyphylline;Figure 1), one of the N7-substituted theophylline derivatives, has been used clinically as a bronchodilator for over 50 years. Although the bronchodilatory effects with diprophylline are ~10 times less than the effects with theophylline,the half-life of diprophylline in plasma is much shorter than that of theophylline. Previous studies have suggested that, in both humans and experimental animals, the dispositions of these two drugs are quite different: theophylline is extensively metabolized by the hepatic mixed.function oxidase system and only 10% of unchanged theophylline is excreted in urine, whereas diprophylline is excreted into the urine almost completely in unchanged form by glomerular filtration and tubular secretion. The previous studys also showed that diprophylline is excreted by the kidneys and that its renal clearance is about seven times greater than the glomerular filtration rate(GFR),a fact indicating that active tubular secretion is the main mechanism of renal excretion of diprophylline in rats. In addition, May and Jarboe reported that the renal clearance of diprophylline decreases with coadministration of probenecid, which is known as an inhibitor of anion transport in the renal tubules of humans.[1]

Pharmacodynamics

Diprophylline, a xanthine derivative, is a bronchodilator used for relief of acute bronchial asthma and for reversible bronchospasm associated with chronic bronchitis and emphysema. Diprophylline is a xanthine derivative with pharmacologic actions similar to theophylline and other members of this class of drugs. Its primary action is that of bronchodilation, but it also exhibits peripheral vasodilatory and other smooth muscle relaxant activity to a lesser degree. The dose-independent pharmacokinetic characteristics of diprophylline are probably due to the high degree of active transport of diprophylline in the renal transport system. Moreover, the observed competitive inhibitory effect of probenecid, which has a low Ki, on the renal secretion of diprophylline indicates that coadministration of diprophylline and probenecid may increase diprophylline activity by decreasing the elimination of diprophylline in plasma.

Mechanism of action

The bronchodilatory action of Diprophylline, as with other xanthines, is thought to be mediated through competitive inhibition of phosphodiesterase with a resulting increase in cyclic AMP producing relaxation of bronchial smooth muscle as well as antagonism of adenosine receptors.

Route of elimination

Diprophylline exerts its bronchodilatory effects directly and, unlike theophylline, is excreted unchanged by the kidneys without being metabolized by the liver. Approximately 88% of a single oral dose can be recovered from the urine unchanged.

Potential role of diprophylline in COVID-19

Human coronaviruses (HCoVs) have evolved to be highly replicating pathogenic viruses. SARS-CoV-2 responsible for the COVID-19 pandemic is one of the most lethal outbreaks of HCoV and there is a pressing need for pan-HCoV therapies. The Mpro is largely conserved among HCoV and is responsible for processing the non-structural polypeptides into functional proteins and hence considered a potential therapeutic target. 

This study identified diprophylline that can block the catalytic dyad of Mpro from tested HCoV strains (SARSCoV-2, HCOV-NL63, HCoV-229E, and HCoV-OC43) by virtual screening. Importantly, the diprophylline dose-dependently inhibited the tested four coronaviruses in cell culture models at variable concentrations ranging from1 to 1000 μm. The EC50 and CC50 values indicate a therapeutic efficacy and safety against virus and cell lines,respectively. The EC50 value for HCoV-NL63, HCoV-229E, HCoV-OC43 and SARS-CoV-2 was obtained as47.59, 88.60, 100.2, and 56.8 μm, respectively. On the other hand, the CC50 value for diprophylline was obtained as over 500 μm in SARS-CoV-2 infected Calu-3 cells while over 1000 μm for different cell lines infected with the other three strains. Interestingly, the antiviral effects of diprophylline were additive with molnupiravir, a recently authorized ribonucleoside analog that inhibits the replication of SARS-CoV-2.Recently, many investigators, including us, have studied the therapeutic potential of plant-based natural products including Xanthine derivatives, against the Mpro and other targets of SARS-CoV-2 and highly coveted its role in treatment of COVID-19. Xanthine derivatives have been shown to have the anti-inflammatory and immunomodulatory properties and are used in the treatment of respiratory diseases. Previous studies report the potential inhibitory effect of such xanthine derivatives, mainly pentoxifylline and caffeine-containing compoundsagainst the Mpro of SARS-CoV-2. Diprophylline is well tolerated and has known drug efficacy as a potent bronchodilator to manage asthma and bronchitis. Diprophylline may act synergistically to provide two clinical benefits: alleviating symptoms of bronchospasm and as an antiviral. Collectively, our molecular docking and in vitro experimental findings demonstrated the pan-coronavirus antiviral activity of diprophylline and support potential repurposing for treating coronavirus-infected patients. However, further validation in animal models is warranted before clinical applications.[2]

References

1.Nadai M, Apichartpichean R, Hasegawa T, Nabeshima T. Pharmacokinetics and the effect of probenecid on the renal excretion mechanism of diprophylline. J Pharm Sci. 1992;81(10):1024-1027. doi:10.1002/jps.2600811014

2.Wang Y, Rajpoot S, Li P, et al. Repurposing dyphylline as a pan-coronavirus antiviral therapy. Future Med Chem. 2022;14(10):685-699. doi:10.4155/fmc-2021-0311