Pharmacokinetics of guanosine in rats following intravenous or intramuscular administration of a 1:1 mixture of guanosine and acriflavine, a potential antitumor agent

Abstract

A 1:1 mixture of acriflavine (ACF; CAS 8063-24-9) and guanosine is under evaluation in preclinical studies as a possible antitumor agent. Guanosine is known to potentiate the anti-cancer activity of ACF. We therefore investigated the pharmacokinetics of guanosine following administration of the ACF/guanosine mixture in rats. Rats were given guanosine (1 or 5 mg/kg) or ACF/guanosine (2 or 10 mg/kg) by i.v. bolus; or guanosine (3 or 15 mg/kg) or ACF/guanosine (6 or 30 mg/kg) by i.m. injection. We found that guanosine was rapidly cleared from the blood and transferred to tissues after i.m. administration of ACF/guanosine. The mean plasma half-lives (t(1/2)) at the alpha and beta phases were 0.091 and 6.86 h, or 0.09 and 7.51 h at a dose of 1 or 5 mg/kg guanosine, respectively. ACF had no effect on the plasma disappearance of guanosine following either i.v. bolus or i.m. administration of the combination mixture. Moreover, the ACF combination with guanosine did not significantly alter the values of MRT, V(dss), and CL(t) of guanosine. Guanosine exhibited linear pharmacokinetics over the dose range from 1 to 5 mg/kg for i.v. doses and 3 to 15 mg/kg for i.m. doses. The bioavailability of guanosine after i.m. administration was 84% for 3 mg/kg dose and 88% for 15 mg/kg dose. ACF had no effects on biliary and urinary excretion of guanosine after i.m. administration. The cumulative amount of guanosine in urine after i.m. administration was about 5-fold larger than that in bile, indicating that guanosine is mostly excreted into the urine. Guanosine was widely distributed in all tissues examined in this study, but was most highly concentrated in the kidney after i.m. administration, followed by slow excretion to bile or urine. ACF had no effect on the tissue distribution of guanosine following i.m. administration. These characterizations of the pharmacokinetics of guanosine after administration of the ACF/guanosine combination will be useful in providing preclinical and clinical bases for the potential application of this combination to the treatment of cancer.

Guanosine: a Neuromodulator with Therapeutic Potential in Brain Disorders

“…Xanthine levels were higher at liver and kidneys, suggesting that these organs play an important role in the metabolism and possibly excretion of guanosine. This data is supported by a previous study, where [ 3 H]guanosine given via intramuscular was primarily found at animals kidney [ 61 ].…”

Acriflavine, a clinically approved drug, inhibits SARS-CoV-2 and other betacoronaviruses

“…The pharmacokinetics of ACF has been previously reported in the context of its antitumor activity. The published data point to a very fast plasma clearance of ACF by intravenous and intramuscular delivery ( Lee et al., 2007 ; Shin et al., 2008 ). ACF is approved for oral use as a systemic drug against urinary tract infections in Brazil; yet, data on oral bioavailability, pharmacokinetics, and lung concentration levels of ACF are not publicly available.…”

The Guanosine-Adenosine Interaction Exists In Vivo

“…The discussion herein underscores the possibility for therapeutic intervention with either guanosine per se or with drugs that modulate guanosine. In this regard, guanosine could be delivered either intravenously or intramuscularly (Shin et al, 2008) or via intraperitoneal administration (Giuliani et al, 2012). Importantly, the results of the present study demonstrate that guanosine per se has little effect on basal arterial blood pressure or renal blood flow and therefore likely would be safe.…”