Inosine pranobex Other names: Isoprinosine Methisoprinol Inosine acedoben dimepranol

Inosine pranobex is a synthetic purine derivative with immunomodulatory and antiviral properties, which result from an apparent in vivo enhancement of host immune responses due to the drug.

In clinical studies inosine pranobex has been shown to normalise (to the patient’s baseline) a deficient or dysfunctional cell-mediated immunity by evoking a Th1 type response which initiates T lymphocyte maturation and differentiation and potentiation of induced lymphoproliferative responses, in mitogen or antigen-activated cells. Similarly, the drug has been shown to modulate T lymphocyte and natural killer cell cytotoxicity, T8 suppressor and T4 helper cell functions and also to increase the number of IgG and complement surface markers.

Inosine pranobex increases cytokine IL-1 production and enhances IL-2 production, upregulating the expression of the IL-2 receptor in vitro. It significantly increases endogenous IFN-γ secretion and decreases the IL-4 production in vivo. It has also been shown to potentiate neutrophil, monocyte and macrophage chemotaxis and phagocytosis.

In vivo, inosine acedoben dimeparanol enhances potentiation of depressed lymphocytic mRNA protein synthesis and translational ability while inhibiting viral RNA synthesis achieved by yet-to-be-clarified degrees of (1) incorporation of inosine-mediated orotic acid into polyribosomes; (2) inhibition of polyadenylic acid attachment to viral messenger RNA and (3) molecular reorganisation of lymphocyte intramembrane plasma particles (IMP) that results in a nearly threefold increase in density.

Inosine pranobex inhibits cGMP phosphodiesterase only at high concentrations in vitro and at levels not involved in the in vivo immunopharmacological effects.

Each moiety of the drug exhibits separate pharmacological properties.

Absorption

When administered orally in man, inosine pranobex is rapidly and completely absorbed (≥90%) from the gastrointestinal tract and appears in the blood. Similarly, 94-100% of IV values of DIP [N,N-dimethylamino-2-propanol] and PacBA [p-acetamidobenzoic acid] components are recovered in urine after oral administration in Rhesus monkeys.

Distribution

Radiolabelled material was found in the following tissues in order of decreasing specific activity when drug was administered to monkeys: kidneys, lung, liver, heart, spleen, testes, pancreas, brain and skeletal muscle

Metabolism

In human subjects following a 1 g oral dose of inosine pranobex, the following plasma levels were found for DIP and PAcBA, respectively: 3.7μg/ml (2 hours) and 9.4μg/ml (1 hour). In human dose tolerance studies, peak post-dose elevation of uric acid levels as a measurement of drug-derived inosine are not linear and can vary + 10% between 1-3 hours.

Excretion

The 24-hour urinary excretion of PAcBA and its major metabolite under steady-state conditions at 4g per day amounted to approximately 85% of the administered dose. 95% of the DIP-derived radioactivity in urine was recovered as unchanged DIP and DIP N-oxide. The elimination half-life is 3.5 hours for DIP and 50 minutes for PAcBA. The major metabolites in humans are the N-oxide for DIP and the o-acylglucuronide for PAcBA. Because the inosine moiety is degraded by the purine degradation pathway to uric acid, radiolabelled experiments in humans are inappropriate. In animals up to about 70% of the administered inosine can be recovered as urinary uric acid following oral tablet administration and the remainder as the normal metabolites, xanthine and hypoxanthine.

Bioavailability/AUC

Urinary recoveries under steady state conditions of the PAcBA moiety and its metabolite were found to be >90% of the expected value from solution. The recovery of the DIP moiety and its metabolite was >76%. The plasma AUC was >88% for DIP and >77% for PAcBA.

Inosine pranobex showed a low toxicity profile in multivariate acute, subacute and chronic toxicology in mice, rats, dogs, cats and monkeys in doses up to 1500mg/kg/day and produced the lowest acute oral LD₅₀ at 50 times the maximum therapeutic dosage level of 100mg/kg/day.

Long-term toxicology studies in mice and rats have shown no indication of carcinogenic potential.

Standard mutagenicity assays and in vivo studies in mice and rats and in vitro studies in human peripheral blood lymphocytes revealed no aberrant properties.

No evidence of perinatal toxicity, embryotoxicity, teratogenicity or impaired reproductive function in mice, rats and rabbits could be demonstrated in studies with continuous parental dosing of up to 20 times the maximum therapeutically recommended human dose (100 mg/kg/day).