A prodrug is a pharmacological substance (drug) administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and excretion (ADME) optimization. Prodrugs are usually designed to improve oral bioavailability, with poor absorption from the gastrointestinal tract usually being the limiting factor.
Additionally, the use of a prodrug strategy increases the selectivity of the drug for its intended target. An example of this can be seen in many chemotherapy treatments, in which the reduction of adverse effects is always of paramount importance. Drugs used to target hypoxic cancer cells, through the use of redox-activation, utilise the large quantities of reductase enzyme present in the hypoxic cell to bioactivate the drug into its cytotoxic form, essentially activating it. As the prodrug has low cytotoxicity prior to this activation, there is a markedly lower chance of it "attacking" healthy, non-cancerous cells which reduces the side-effects associated with these chemotherapeutic agents.
In rational drug design, the knowledge of both chemical properties likely to improve absorption and the major metabolic pathways in the body is used to modify the structure of new chemical entities for improved bioavailability. Conversely, the creation of prodrugs is sometimes unintentional, for example with serendipitous drug discoveries, where the drug is only later identified as a prodrug after extensive drug metabolism studies.
Prodrugs can be classified into two major types, based on their cellular sites of bioactivation into the final active drug form, with Type I being those that are bioactivated intracellularly (e.g., anti-viral nucleoside analogs, lipid-lowering statins,), and Type II being those that are bioactivated extracellularly, especially in digestive fluids or the systemic circulation (e.g., etoposide phosphate, valganciclovir, fosamprenavir, antibody-, gene- or virus-directed enzyme prodrugs [ADEP/GDEP/VDEP] for chemotherapy or immunotherapy). Both types can be further categorized into Subtypes, i.e. Type IA, IB and Type IIA, IIB, and IIC based on whether or not the intracellular bioactivating location is also the site of therapeutic action, or the bioactivation occurs in the gastrointestinal (GI) fluids or systemic circulation (see Table 1).
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 extracelluarly, 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 fumarate; note the symbol “ - ” applied here). Many ADEPs, VDEPs, GDEPs and futuristic nanoparticle- or nanocarrier-linked drug moieties 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.
Table 1: Classification of prodrugs Type Bioactivation site Subtype Tissue location of bioactivation Examples Type I Intracellular Type IA Therapeutic target tissues/cells Acyclovir, 5-Flurouracil, Cyclophosphamide, Diethylstilbestrol diphosphate, Type I Intracellular Type IB Metabolic tissues (liver, GI mucosal cell,lung etc) Carbamazepine, Captopril, Carisoprodol, Heroin, Molsidomine, Paliperidone, Phenacetin, Primidone, Psilocybin, Suldinac, Tetrahydrofurfuryl disulfide Type II Extracellular Type IIA GI fluids Lisdexamfetamine, Loperamide oxide, Oxyphenisatin, Sulfasalazine Type II Extracellular Type IIB Systemic circulation and Other Extracellular Fluid Compartments Acetylsalicylate, Bacampicillin, Bambuterol, Chloramphenicol succinate,
Dihydropyridine pralixoxime, Dipivefrin, Fosphenytoin
Type II Extracellular Type IIC Therapeutic Target Tissues/Cells ADEPTs, GDEPs, VDEPs
Adapted from Pharmaceuticals (2:77-81, 2009) and Toxicology (236:1-6, 2007).
- 6-Monoacetylmorphine (6-MAM) is a heroin metabolite which converts into active morphine in vivo.
- Carisoprodol is metabolized into meprobamate. Carisoprodol is not a controlled substance in the United States, but meprobamate is classified as a potentially addictive controlled substance that can produce dangerous and painful withdrawal symptoms upon discontinuation of the drug.
- Enalapril is bioactivated by esterase to the active enalaprilat.
- Valaciclovir is bioactivated by esterase to the active aciclovir.
- Fosamprenavir is hydrolysed to the active amprenavir.
- Levodopa is bioactivated by DOPA decarboxylase to the active dopamine.
- Chloramphenicol succinate ester is used as an intravenous prodrug of chloramphenicol, because pure chloramphenicol does not dissolve in water.
- Psilocybin is dephosphorylated to the active psilocin.
- Heroin is deacetylated by esterase to the active morphine.
- Molsidomine is metabolized into SIN-1 which decomposes into the active compound nitric oxide.
- Paliperidone is an atypical antipsychotic for schizophrenia. It is the active metabolite of risperidone.
- Prednisone, a synthetic cortico-steroid drug, is bioactivated by the liver into the active drug prednisolone, which is also a steroid.
- Primidone is metabolized by cytochrome P450 enzymes into phenobarbital, which is major, and phenylethylmalonamide, which is minor.
- Dipivefrine, given topically as an anti-glaucoma drug, is bioactivated to epinephrine.
- Lisdexamfetamine is metabolized in the small intestine to produce dextroamphetamine at a controlled (slow) rate for the treatment of attention-deficit hyperactivity disorder
- Diethylpropion is a diet pill that does not become active as a monoamine releaser or reuptake inhibitor until it has been N-dealkylated to ethylpropion.
- Fesoterodine is an antimuscarinic that is bioactivated to tolterodine.
- Tenofovir disoproxil fumarate is an anti-HIV drug (NtRTI class) that is bioactivated to tenofovir (PMPA).
- ^ see Table 1; Wu,K.M.: A New Classification of Prodrugs: Regulatory Perspectives Pharmaceuticals 2:77-81, 2009.<http://dx.doi.org/10.3390/ph2030077>.
- ^ see Table 1; Wu, K.M.; Farrelly, J.: Regulatory Perspectives of Type II Prodrug Development and Time-Dependent Toxicity Management: Nonclinical Pharm/Tox Analysis and the Role of Comparative Toxicology. Toxicology 2007, 236, 1–6. <http://dx.doi.org/10.1016/j.tox.2007.04.005>
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