528:
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.,
548:- 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.
527:
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
304:
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.
205:, 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 its
54:. 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 like
1113:
667:
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".
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191:, 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,
62:
1099:
993:"Regulatory perspectives of Type II prodrug development and time-dependent toxicity management: nonclinical Pharm/Tox analysis and the role of comparative toxicology"
195:, 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.
39:
drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug is absorbed, distributed, metabolized, and excreted (
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containing specialized nontoxic protective groups used in a transient manner to alter or to eliminate undesirable properties in the parent molecule.
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Approximately 10% of all marketed drugs worldwide can be considered prodrugs. Since 2008, at least 30 prodrugs have been approved by the
277:
Type I prodrugs are bioactivated inside the cells (intracellularly). Examples of these are anti-viral nucleoside analogs that must be
1164:
898:
651:
590:
Rautio J, Meanwell NA, Di L, Hageman MJ (August 2018). "The expanding role of prodrugs in contemporary drug design and development".
292:. Examples of Type II prodrugs are salicin (described above) and certain antibody-, gene- or virus-directed enzyme prodrugs used in
1217:
273:
Prodrugs can be classified into two major types, based on how the body converts the prodrug into the final active drug form:
355:
103:(sugar derivatives) of the active agent, which are hydrolyzed in the intestines to release the active and more bioavailable
218:
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Type II prodrugs are bioactivated outside cells (extracellularly), especially in digestive fluids or in the body's
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36:
702:
Stella VJ, Charman WN, Naringrekar VH (May 1985). "Prodrugs. Do they have advantages in clinical practice?".
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639:
221:. Seven prodrugs were approved in 2015 and six in 2017. Examples of recently approved prodrugs are such as
1191:
51:
532:; note the symbol " - " applied here). Many antibody- virus- and gene-directed enzyme prodrug therapies (
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in 1897, is a synthetic prodrug of salicylic acid. However, in other cases, such as
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782:"Terminology for biorelated polymers and applications (IUPAC Recommendations 2012)"
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Vert M, Doi Y, Hellwich KH, Hess M, Hodge P, Kubisa P, Rinaudo M, Schué F (2012).
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747:"Glossary of terms used in medicinal chemistry (IUPAC Recommendations 1998)"
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in 1932), must be cleaved in the body to release the active molecule,
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58:, which can have severe unintended and undesirable side effects.
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Compound that is metabolized into a pharmacologically active drug
40:
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Systemic circulation and other extracellular fluid compartments
181:. Since that time, many other examples have been identified.
69:
Compound that undergoes biotransformation before exhibiting
1033:"A New Classification of Prodrugs: Regulatory Perspectives"
939:"A New Classification of Prodrugs: Regulatory Perspectives"
99:
Many herbal extracts historically used in medicine contain
745:
Wermuth CG, Ganellin CR, Lindberg P, Mitscher LA (1998).
201:, another non-sedating antihistamine, is the prodrug of
1087:
Special Issue on
Prodrugs: from Design to Applications
640:"Chapter 10.5: Elimination (Metabolism and Excretion)"
381:
Metabolic tissues (liver, GI mucosal cell, lung etc.)
1258:
1200:
1127:
150:) that are more active than the parent compound.
67:
50:when a drug itself is poorly absorbed from the
1107:
8:
913:UK Medicines Information Pharmacists Group.
915:New Medicines on the Market: Desloratadine.
1114:
1100:
1092:
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1048:
964:
954:
863:
840:"The discovery of aspirin: a reappraisal"
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638:Hacker M, Messer WS, Bachmann KA (2009).
633:
631:
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209:, desloratadine, are currently marketed.
35:(i.e., converted within the body) into a
1243:List of medicine contamination incidents
437:
333:
307:
153:The first synthetic antimicrobial drug,
115:that is cleaved by esterases to release
1122:Combined substance use and adulteration
579:
46:Prodrugs are often designed to improve
123:, acetylsalicylic acid, first made by
986:
984:
932:
930:
644:Pharmacology: Principles and Practice
7:
1277:List of reagent testing color charts
646:. Academic Press. pp. 216–217.
585:
583:
146:to form sugar derivatives (morphine-
1165:List of polysubstance combinations
14:
85:: Prodrugs can thus be viewed as
1218:Counterfeit illegal drug selling
991:Wu KM, Farrelly JG (July 2007).
716:10.2165/00003495-198529050-00002
503:Therapeutic target tissues/cells
340:Therapeutic target tissues/cells
323:Tissue location of bioactivation
23:is a pharmacologically inactive
281:and the lipid-lowering statins.
592:Nature Reviews. Drug Discovery
356:diethylstilbestrol diphosphate
1:
669:Current Medicinal Chemistry
309:Classification of prodrugs
139:, the administered drug is
1322:
1150:Combined drug intoxication
790:Pure and Applied Chemistry
752:Pure and Applied Chemistry
681:10.2174/092986709789712835
1009:10.1016/j.tox.2007.04.005
856:10.1136/bmj.321.7276.1591
478:chloramphenicol succinate
434:
330:
187:, the first non-sedating
1182:Polysubstance dependence
803:10.1351/PAC-REC-10-12-04
568:Neurotransmitter prodrug
157:, discovered in 1909 by
37:pharmacologically active
27:or compound that, after
1238:Counterfeit medications
766:10.1351/pac199870051129
317:Bioactivation site
1128:Combined substance use
1031:Wu KM (October 2009).
937:Wu KM (October 2009).
288:, particularly in the
91:
52:gastrointestinal tract
1223:Clandestine chemistry
558:Precursor (chemistry)
263:serdexmethylphenidate
243:aripiprazole lauroxil
161:in the laboratory of
79:: Modified from ref.
890:Acetylsalicylic acid
530:tenofovir disoproxil
251:latanoprostene bunod
227:gabapentin enacarbil
225:(approved in 2010),
223:dabigatran etexilate
850:(7276): 1591–1594.
604:10.1038/nrd.2018.46
310:
235:tedizolid phosphate
113:β-D-glucopyranoside
920:2007-10-11 at the
838:Sneader W (2000).
447:Loperamide oxide,
308:
286:circulatory system
1286:
1285:
1160:Polysubstance use
1135:Active metabolite
1050:10.3390/ph2030077
956:10.3390/ph2030077
887:Schrör K (2009).
675:(33): 4481–4489.
520:
519:
207:active metabolite
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1299:Pharmacokinetics
1155:Drug interaction
1145:Combination drug
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813:. Archived from
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759:(5): 1129–1143.
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490:lisdexamfetamine
466:Acetylsalicylate
352:cyclophosphamide
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107:. For example,
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239:isavuconazonium
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213:Recent prodrugs
173:(discovered by
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71:pharmacological
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48:bioavailability
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269:Classification
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175:Gerhard Domagk
159:Sahachiro Hata
125:Felix Hoffmann
117:salicylic acid
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1172:Polypharmacy
1043:(3): 77–81.
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1003:(1–2): 1–6.
1000:
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949:(3): 77–81.
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822:. Retrieved
815:the original
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707:
703:
697:
672:
668:
662:
643:
595:
591:
546:nanoparticle
526:
486:fosphenytoin
435:Type II
409:paliperidone
393:carisoprodol
348:fluorouracil
303:
294:chemotherapy
272:
216:
197:
193:fexofenadine
183:
169:, the first
163:Paul Ehrlich
155:arsphenamine
152:
148:glucuronides
98:
86:
82:
81:
76:
75:
70:
68:
56:chemotherapy
45:
20:
18:
494:pralidoxime
405:leflunomide
401:molsidomine
261:(2020) and
259:tozinameran
185:Terfenadine
33:metabolized
1293:Categories
1234:Medicines
1210:Drug fraud
997:Toxicology
924:June 2001.
824:2013-07-29
574:References
563:Toxication
482:dipivefrin
474:bambuterol
421:psilocybin
413:phenacetin
372:zidovudine
231:sofosbuvir
199:Loratadine
171:sulfa drug
101:glycosides
65:definition
25:medication
1073:; Table 1
1021:; Table 1
893:. Wiley.
732:195692168
444:GI fluids
417:primidone
389:captopril
368:mitomycin
344:Aciclovir
326:Examples
247:selexipag
167:prontosil
144:activated
73:effects.
1304:Prodrugs
1250:Impurity
1177:Polypill
1069:27713225
1017:17507137
975:27713225
918:Archived
874:11124191
811:98107080
689:19835561
620:19489166
612:29700501
552:See also
523:Subtypes
500:Type IIC
459:Type IIB
441:Type IIA
425:sulindac
265:(2021).
257:(2018),
253:(2017),
249:(2015),
245:(2015),
241:(2015),
237:(2014),
233:(2013),
229:(2011),
137:morphine
105:aglycone
1192:Synergy
1187:Prodrug
1060:3978533
966:3978533
865:1119266
724:3891303
378:Type IB
337:Type IA
320:Subtype
133:codeine
121:Aspirin
109:salicin
95:History
21:prodrug
1228:Lacing
1140:Codrug
1067:
1057:
1015:
973:
963:
897:
872:
862:
809:
730:
722:
687:
650:
618:
610:
542:GDEPTs
538:VDEPTs
534:ADEPTs
515:VDEPTs
511:GDEPTs
507:ADEPTs
397:heroin
360:L-DOPA
331:Type I
83:Note 2
77:Note 1
29:intake
818:(PDF)
807:S2CID
785:(PDF)
728:S2CID
704:Drugs
616:S2CID
290:blood
129:Bayer
111:is a
87:drugs
63:IUPAC
31:, is
1065:PMID
1013:PMID
971:PMID
895:ISBN
870:PMID
720:PMID
685:PMID
648:ISBN
608:PMID
314:Type
135:and
43:).
41:ADME
1055:PMC
1045:doi
1005:doi
1001:236
961:PMC
951:doi
860:PMC
852:doi
848:321
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799:doi
761:doi
712:doi
677:doi
600:doi
296:or
219:FDA
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787:.
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