Ribavirin is a pro-drug, meaning that it is a chemical precursor for the actual pharmacologically active molecule. When the pro-drug is administered, the body converts it into the desired chemical. Ribavirin is activated by cellular kinases which change it into the 5' triphosphate nucleotide. In this form it interferes with aspects of RNA metabolism related to viral replication. A number of mechanisms have been proposed for this (see Mechanisms of Action, below) but none of these is proven. More than one mechanism may be active.
In the U.K. & the U.S. the oral (capsule or tablet) form of ribavirin is used in the treatment of hepatitis C, in combination with pegylated interferon drugs. The aerosol form has been used in the past to treat respiratory syncytial virus-related diseases in children. However, its efficacy has been called into question by multiple studies, and most institutions no longer use it. In Mexico, ribavirin ("ribavirina") has been sold for use against influenza.
The primary observed serious adverse side-effect of ribavirin is hemolytic anemia, which may worsen preexisting cardiac disease. The mechanism for this effect is unknown. It is dose-dependent and may sometimes be compensated by decreasing dose. Ribavirin is also a teratogen in some animals species and thus poses a theoretical reproductive risk in humans, remaining a hazard as long as the drug is present, which can be as long as 6 months after a course of the drug has ended.
In Mexico, oral ribavirin has been available since the 1980s as an over-the-counter drug ("ribavirina," ICN pharmaceuticals Spanish tradename Vilona), for treating influenza. In this form it was occasionally brought into the U.S. for HIV/AIDS patients. However, ribavirin has proven to have little if any clinical usefulness against HIV, and it can greatly increase blood levels and also toxicity of the HIV antiviral didanosine (ddI, Videx). Other interactions with nucleoside antivirals for HIV should be considered when HIV/AIDS patients use ribavirin to treat hepatitis C (see "aidsinfo" external link).
In 1972 it was reported that ribavirin was active against a variety of RNA and DNA viruses in culture and in animals, without undue toxicity. Ribavirin protected mice against mortality from both A and B strains of influenza, and ICN originally planned to market it as an anti-influenza drug. Results in human trials against experimental influenza infection were mixed, however, and the FDA ultimately did not approve this indication for ribavirin use in humans, thereby causing a severe financial shock to ICN.
Although ICN was allowed in 1980 to market ribavirin, in inhalant form, for RSV infection in children, the U.S. market for this indication was small. By the time oral ribavirin was finally approved by the FDA as part of a combination treatment (with interferon) for hepatitis C in 1998, the original ICN patents on ribavirin itself had expired, and (notwithstanding subsequent patent disputes) ribavirin had become essentially a generic drug.
Ribavirin's present generic status is expected to slow research into new uses, however.
Classically ribavirin is prepared from natural D-ribose by blocking the 2', 3' and 5' OH groups with benzyl groups, then derivatizing the 1' OH with an acetyl group which acts as a suitable leaving group upon nucleophilic attack. The ribose 1' carbon attack is accomplished with 1,2,4 triazole-3-carboxymethyl ester, which directly attaches the 1' nitrogen of the triazole to the 1' carbon of the ribose, in the proper 1-β-D isomeric position. The bulky benzyl groups hinder attack at the other sugar carbons. Following purification of this intermediate, treatment with ammonia in methanolic conditions then simultaneously deblocks the ribose hydroxyls, and converts the triazole carboxymethyl ester to the carboxamide. Following this step, ribavirin may be recovered in good quantity by cooling and crystallization.
Derivatization of the triazole 5' carbon, or replacement of it with a nitrogen (i.e., the 1,2,4,5 tetrazole 3-carboxamide) also results in substantial loss of activity, as does alkyl derivatization of the 3' carboxamide nitrogen.
The 2' deoxyribose version of ribavirin (the DNA nucleoside analogue) is not active as an antiviral, suggesting strongly that ribavirin requires RNA-dependent enzymes for its antiviral activity.
Antiviral activity is retained for acetate and phosphate derivation of the ribose hydroxyls, including the triphosphate and 3', 5' cyclic phosphates, but these compounds are no more active than the parent molecule, reflecting the high efficiency of esterase and kinase activity in the body.viramidine (also "Ribamidine"). This drug shows a similar spectrum of antiviral activity to ribavirin, which is not surprising as it is now known to be a pro-drug for ribavirin. Viramidine, however, has useful properties of less erythrocyte-trapping and better liver-targeting than ribavirin. The first property is due to viramidine's basic amidine group which inhibits drug entry into RBCs, and the second property is probably due to increased concentration of the enzymes which convert amidine to amide, in liver tissue. Viramidine is in phase III human trials and may one day be used in place of ribavirin, at least against certain kinds of viral hepatitis (see links in viramidine article). Viramidine's slightly superior toxicological properties may eventually cause it to replace ribavirin in all uses of ribavirin. For example, see PMID 16087250.
Ribavirin 5' mono- di- and tri-phosphates, in addition, are all inhibitors of certain viral RNA-dependent RNA polymerases which are a feature of RNA viruses (save for retroviruses).
Neither of these mechanisms explains ribavirin's effect on many DNA viruses, which is more of a mystery. Ribavirin 5'-monophosphate inhibits cellular inosine monophosphate dehydrogenase, thereby depleting intracellular pools of GTP. This mechanism may be useful in explaining the drug's general cytotoxic and anti-DNA replication effect (i.e. its toxicity) as well as some effect on DNA viral replication.
Ribavirin is an inhibitor of some viral RNA guanylyl transferase and (guanine-7N-)-methyl transferase enzymes, and this may contribute to a defective 5'-cap structure of viral mRNA transcripts and therefore inefficient viral translation for certain DNA viruses, such as vaccinia virus (a complex DNA virus). It has been suggested that incorporation of ribavirin into the 5' end of mRNA transcripts would mimic the 7-methyl guanosine endcap of cellular mRNAs, causing poor cellular translation of these. This would be a cell-toxic effect, but it does not seem to be important at therapeutic ribavirin concentrations. Any difference between cellular and viral enzyme handling of ribavirin-containin mRNA transcripts, is a potential mechanism of differential inhibition of ribavirin to translation of mRNAs from viruses (including DNA viruses).
Finally, ribavirin is known to enhance host T-cell-mediated immunity against viral infection through helping to switch the host T-cell phenotype from type 2 to type 1. This may explain rivavirin's antiviral activity against some viruses such as hepatitis C, at doses which do not clearly interfere with replication of the virus when used without interferon (see hepcassoc.org external link below).
Ribavirin is widely distributed in all tissues, including the CSF and brain. The pharmacokinetics of ribavirin is dominated by trapping of the phosphated form inside cells, particularly red blood cells (RBCs) which lack the enzyme to remove the phosphate once it has been added by kinases, and therefore attain high concentrations of the drug. Most of the kinase activity which converts the drug to active nucleotide form, is provided by adenine kinase. This enzyme is more active in virally infected cells.
The volume of distribution of ribavirin is large (2000 L/kg) and the length of time the drug is trapped varies greatly from tissue to tissue. The mean half-life for multiple doses in the body is about 12 days, but very long-term kinetics are dominated by the kinetics of RBCs (half-life 40 days). RBCs store ribavirin for the lifetime of the cells, releasing it into the body's systems when old cells are degraded in the spleen.
About a third of absorbed ribavirin is excreted into the urine unchanged, and the rest is excreted into urine as the de-ribosylated base 1,2,4-triazole 3-carboxamide, and the oxidation product of this, 1,2,4- triazole 3-carboxylic acid.
Ribavirin is not substantially incorporated into DNA, but does have a dose-dependent inhibiting effect on DNA synthesis, as well as having other effects on gene-expression. Possibly for these reasons, significant teratogenic effects have been noted in all non-primate animal species on which ribavirin has been tested. Ribavirin did not produce birth defects in baboons, but this should not be an indication that it is safe in humans. Therefore, two simultaneous forms of birth control are recommended during treatment of either partner and continued for six months after treatment. Women who are pregnant or planning to become pregnant are advised not to take ribavirin. Of special concern as regards teratogenicity is the ribavirin's long half-life in the body. Red blood cells (erythrocytes) concentrate the drug and are unable to excrete it, so this pool is not completely eliminated until all red cells have turned over, a process estimated to take as long as 6 months. Thus in theory, ribavirin might remain a reproductive hazard for as long as 6 months after a course of the drug has ended. Drug packaging information materials in the U.S. now reflect this warning.
Ribavirin should not be given with zidovudine because of the increased risk of anaemia; concurrent use with didanosine should likewise be avoided because of an increased risk of mitochondrial toxicity.
ICN Ordered to Cut Drug's Price in Canada, but Disputes It.(Originated from The Orange County Register, Calif.)
Jul 30, 1996; COSTA MESA, CalifJul. 30--A Canadian government agency ruled Monday that ICN Pharmaceuticals Inc. vastly overpriced a drug to...