Prodrug
Aprodrugis a pharmacologically inactivemedicationor compound that, afterintake,ismetabolized(i.e., converted within the body) into apharmacologically activedrug.[1][2]Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug is absorbed, distributed, metabolized, and excreted (ADME).[3][4]
Prodrugs are often designed to improvebioavailabilitywhen a drug itself is poorly absorbed from thegastrointestinal tract.[2]A prodrug may be used to improve how selectively the drug interacts with cells or processes that are not its intended target. This reduces adverse or unintended effects of a drug, especially important in treatments likechemotherapy,which can have severe unintended and undesirable side effects.
Compound that undergoes biotransformation before exhibitingpharmacologicaleffects.
Note 1:Modified from ref.[5]
Note 2:Prodrugs can thus be viewed asdrugscontaining specialized nontoxic protective groups used in a transient manner to alter or to eliminate undesirable properties in the parent molecule.[6]
History
[edit]Many herbal extracts historically used in medicine containglycosides(sugar derivatives) of the active agent, which are hydrolyzed in the intestines to release the active and more bioavailableaglycone.For example,salicinis aβ-D-glucopyranosidethat is cleaved by esterases to releasesalicylic acid.Aspirin,acetylsalicylic acid, first made byFelix HoffmannatBayerin 1897, is a synthetic prodrug of salicylic acid.[7][8]However, in other cases, such ascodeineandmorphine,the administered drug isenzymaticallyactivatedto form sugar derivatives (morphine-glucuronides) that are more active than the parent compound.[2]
The first synthetic antimicrobial drug,arsphenamine,discovered in 1909 bySahachiro Hatain the laboratory ofPaul Ehrlich,is not toxic to bacteria until it has been converted to an active form by the body. Likewise,prontosil,the firstsulfa drug(discovered byGerhard Domagkin 1932), must be cleaved in the body to release the active molecule,sulfanilamide.Since that time, many other examples have been identified.
Terfenadine,the first non-sedatingantihistamine,had to be withdrawn from the market because of the small risk of a serious side effect. However, terfenadine was discovered to be the prodrug of the active molecule,fexofenadine,which does not carry the same risks as the parent compound. Therefore, fexofenadine could be placed on the market as a safe replacement for the original drug.
Loratadine,another non-sedating antihistamine, is the prodrug ofdesloratadine,which is largely responsible for the antihistaminergic effects of the parent compound. However, in this case the parent compound does not have the side effects associated with terfenadine, and so both loratadine and itsactive metabolite,desloratadine, are currently marketed.[9]
Recent prodrugs
[edit]Approximately 10% of all marketed drugs worldwide can be considered prodrugs. Since 2008, at least 30 prodrugs have been approved by theFDA.[1]Seven prodrugs were approved in 2015 and six in 2017. Examples of recently approved prodrugs are such asdabigatran etexilate(approved in 2010),gabapentin enacarbil(2011),sofosbuvir(2013),tedizolid phosphate(2014),isavuconazonium(2015),aripiprazole lauroxil(2015),selexipag(2015),latanoprostene bunod(2017),benzhydrocodone(2018),tozinameran(2020) andserdexmethylphenidate(2021).
Classification
[edit]Prodrugs can be classified into two major types,[10]based on how the body converts the prodrug into the final active drug form:
- Type I prodrugs are bioactivated inside the cells (intracellularly). Examples of these are anti-viral nucleoside analogs that must bephosphorylatedand the lipid-lowering statins.
- Type II prodrugs are bioactivated outside cells (extracellularly), especially in digestive fluids or in the body'scirculatory system,particularly in theblood.Examples of Type II prodrugs are salicin (described above) and certain antibody-, gene- or virus-directed enzyme prodrugs used inchemotherapyorimmunotherapy.
Both major types can be further categorized into subtypes, based on factors such as (Type I) whether the intracellular bioactivation location is also the site of therapeutic action, or (Type 2) whether or not bioactivation occurs in the gastrointestinal fluids or in the circulation system.
| Type | Bioactivation site | Subtype | Tissue location of bioactivation | Examples |
|---|---|---|---|---|
| Type I | Intracellular | Type IA | Therapeutic target tissues/cells | Aciclovir,fluorouracil,cyclophosphamide,diethylstilbestrol diphosphate,L-DOPA,mercaptopurine,mitomycin,zidovudine |
| Type IB | Metabolic tissues (liver, GI mucosal cell, lung etc.) | Carbamazepine,captopril,carisoprodol,heroin,molsidomine,leflunomide,paliperidone,phenacetin,primidone,psilocybin,sulindac,fursultiamine | ||
| Type II | Extracellular | Type IIA | GI fluids | Loperamide oxide,oxyphenisatin,sulfasalazine |
| Type IIB | Systemic circulation and other extracellular fluid compartments | Acetylsalicylate,bacampicillin,bambuterol,chloramphenicol succinate,dipivefrin,fosphenytoin,lisdexamfetamine,pralidoxime | ||
| Type IIC | Therapeutic target tissues/cells | ADEPTs,GDEPTs,VDEPTs |
Subtypes
[edit]Type IA prodrugs include many antimicrobial and chemotherapy agents (e.g., 5-flurouracil). Type IB agents rely on metabolic enzymes, especially in hepatic cells, to bioactivate the prodrugs intracellularly to active drugs. Type II prodrugs are bioactivated extracellularly, either in the milieu of GI fluids (Type IIA), within the systemic circulation and/or other extracellular fluid compartments (Type IIB), or near therapeutic target tissues/cells (Type IIC), relying on common enzymes such as esterases and phosphatases or target directed enzymes. Importantly, prodrugs can belong to multiple subtypes (i.e., Mixed-Type). A Mixed-Type prodrug is one that is bioactivated at multiple sites, either in parallel or sequential steps. For example, a prodrug, which is bioactivated concurrently in both target cells and metabolic tissues, could be designated as a "Type IA/IB" prodrug (e.g., HMG Co-A reductase inhibitors and some chemotherapy agents; note the symbol "/" applied here). When a prodrug is bioactivated sequentially, for example initially in GI fluids then systemically within the target cells, it is designated as a "Type IIA-IA" prodrug (e.g.,tenofovir disoproxil;note the symbol "-" applied here). Many antibody- virus- and gene-directed enzyme prodrug therapies (ADEPTs,VDEPTs,GDEPTs) and proposednanoparticle- or nanocarrier-linked drugs can understandably be Sequential Mixed-Type prodrugs. To differentiate these two Subtypes, the symbol dash "-" is used to designate and to indicate sequential steps of bioactivation, and is meant to distinguish from the symbol slash "/" used for the Parallel Mixed-Type prodrugs.[11][12]
See also
[edit]References
[edit]- ^abRautio J, Meanwell NA, Di L, Hageman MJ (August 2018). "The expanding role of prodrugs in contemporary drug design and development".Nature Reviews. Drug Discovery.17(8): 559–587.doi:10.1038/nrd.2018.46.PMID29700501.S2CID19489166.
- ^abcHacker M, Messer WS, Bachmann KA (2009)."Chapter 10.5: Elimination (Metabolism and Excretion)".Pharmacology: Principles and Practice.Academic Press. pp. 216–217.ISBN978-0080919225.
- ^Malhotra B, Gandelman K, Sachse R, Wood N, Michel MC (2009). "The design and development of fesoterodine as a prodrug of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of tolterodine".Current Medicinal Chemistry.16(33): 4481–4489.doi:10.2174/092986709789712835.PMID19835561.
- ^Stella VJ, Charman WN, Naringrekar VH (May 1985). "Prodrugs. Do they have advantages in clinical practice?".Drugs.29(5): 455–473.doi:10.2165/00003495-198529050-00002.PMID3891303.S2CID195692168.
- ^Wermuth CG, Ganellin CR, Lindberg P, Mitscher LA (1998)."Glossary of terms used in medicinal chemistry (IUPAC Recommendations 1998)".Pure and Applied Chemistry.70(5): 1129–1143.doi:10.1351/pac199870051129.
- ^Vert M, Doi Y, Hellwich KH, Hess M, Hodge P, Kubisa P, Rinaudo M, Schué F (2012)."Terminology for biorelated polymers and applications (IUPAC Recommendations 2012)"(PDF).Pure and Applied Chemistry.84(2): 377–410.doi:10.1351/PAC-REC-10-12-04.S2CID98107080.Archived fromthe original(PDF)on 2015-03-19.Retrieved2013-07-29.
- ^Sneader W (2000)."The discovery of aspirin: a reappraisal".BMJ.321(7276): 1591–1594.doi:10.1136/bmj.321.7276.1591.PMC1119266.PMID11124191.
- ^Schrör K (2009).Acetylsalicylic acid.Wiley.ISBN978-3527321094.
- ^UK Medicines Information Pharmacists Group.New Medicines on the Market: Desloratadine.Archived2007-10-11 at theWayback MachineJune 2001.
- ^abWu KM (October 2009)."A New Classification of Prodrugs: Regulatory Perspectives".Pharmaceuticals.2(3): 77–81.doi:10.3390/ph2030077.PMC3978533.PMID27713225.
- ^abWu KM, Farrelly JG (July 2007)."Regulatory perspectives of Type II prodrug development and time-dependent toxicity management: nonclinical Pharm/Tox analysis and the role of comparative toxicology".Toxicology.236(1–2): 1–6.doi:10.1016/j.tox.2007.04.005.PMID17507137.;Table 1
- ^Wu KM (October 2009)."A New Classification of Prodrugs: Regulatory Perspectives".Pharmaceuticals.2(3): 77–81.doi:10.3390/ph2030077.PMC3978533.PMID27713225.;Table 1