Aprodrug is a pharmacologically inactivemedication or compound that, afterintake, ismetabolized (i.e., converted within the body) into apharmacologically active drug.[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 improvebioavailability when 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 exhibitingpharmacological effects.
Note 1: Modified from ref.[5]
Note 2: Prodrugs can thus be viewed asdrugs containing specialized nontoxic protective groups used in a transient manner to alter or to eliminate undesirable properties in the parent molecule.[6]
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,salicin is aβ-D-glucopyranoside that is cleaved by esterases to releasesalicylic acid.Aspirin, acetylsalicylic acid, first made byFelix Hoffmann atBayer in 1897, is a synthetic prodrug of salicylic acid.[7][8] However, in other cases, such ascodeine andmorphine, the administered drug isenzymaticallyactivated to form sugar derivatives (morphine-glucuronides) that are more active than the parent compound.[2]
The first synthetic antimicrobial drug,arsphenamine, discovered in 1909 bySahachiro Hata in 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 Domagk in 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Terfenadine, the first non-sedatingantihistamine, had to be withdrawn from the market because of the small risk of a serious side effect.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]
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).
Prodrugs can be classified into two major types,[10] based on how the body converts the prodrug into the final active drug form:
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,Hypoxia-activated prodrugs |
| 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 |
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]