Prodrugs

 chemicals with little or no

pharmacological activity, undergoing
biotransformation to a therapeutically
active metabolite.
 Prodrugs are inactive but are converted
in vivo to active cytotoxic compounds.
 Conversion to the active form can
occur by different mechanisms,
A diagram showing the prodrug concept, Prodrugs from
particularly by the action of specific Serendipity to Design by Computational Chemistry Methods
Rafik Karaman, Al-Quds J Acad Res 2021: 1(1):6-8
enzymes. https://doi.org/
• Antibody-directed enzyme prodrug therapy (ADEPT) involves prodrug-
activating enzymes targeted to tumours using monoclonal antibodies
against tumour-associated antigens before the administration

The basic principle of ADEPT, Antibody Directed Enzyme Prodrug

Therapy and Translational Therapeutics Research Group
.
 Classification of Prodrug

1. Based on research-related criteria

 Intentional prodrugs
 Fortuitous prodrugs

2. Based on chemical argument

 Carrier-linked prodrug
 Bioprecursors
 Macromolecular prodrugs
 Drug–antibody conjugates
Advantage of Prodrug

Ferreira, E.I. (2020). Prodrug Design to Enhance Bioavailability and Systemic Delivery. In:
Lai, WF. (eds) Systemic Delivery Technologies in Anti-Aging Medicine: Methods and
Applications. Healthy Ageing and Longevity, vol 13. Springer, Cham.
 Principal prodrug families of anticancer
5-Fluorouracil prodrugs
 5-FU remains one of the most commonly
prescribed chemotherapeutic agents in cancer
treatment
 Can be used single in colorectal cancer and as
part of combination regimens for breast, head
and/or neck, and upper gastrointestinal 5-Fluorouracil

malignancies.
Route of administration

 Can be administered daily and weekly by iv

bolus as well as by continuous i.v. infusion.
 Continuous i.v. infusion enables response rates
to be improved with fewer side effects
compared with i.v. bolus dosing. 5-Fluorouracil
Drawback of 5 Fluorouracil
 relatively toxic compound causing myelosuppression, oral mucositis, nausea, diarrhoea and
vomiting; in the case of continuous regimen, the hand–foot syndrome (dermal pain in hands and
foot) and cardiotoxicity for less than 10% of patients.
 Phosphorylation of 5-FU in the digestive tract may cause Gastrointestinal disorder
 Short half life
 low i.v. bioavailability due to the activity of dihydropyrimidine dehydrogenase (DPD) enzyme
 tumours with strong expression of thymidine phosphorylase (TP) or low reserves of reduced
folates may cause resistance
 Plasma levels of 5-FU are unpredictable after oral administration with marked intra- and inter-
individual differences due to the variable activity of DPD in the gastrointestinal mucosa
 In order to overcome the above problems the prodrug of 5 FU to be developed
 The prodrugs of 5-FU are characterized by a pyrimidine ring with a fluorine
atom in position 5.
 Their main benefit is related to the oral route of administration as well as
designed to be well absorbed intact from the gastrointestinal tract and
enzymatically converted into 5-FU in the liver or within the tumour itself to
expose the tumour to 5-FU for a longer time but at lower concentrations than
those observed after an i.v. bolus, hence minimizing toxicity.
 Generation of 5-FU prodrugs
1st generation

5-fluoro-20-deoxyuridine (5-
FdUrd; Floxuridine1).
 main limitation of 5’d 5-FUrd derives from
its gastrointestinal toxicity, attributed to
5-fluoro-20-deoxyuridine
liberation of 5- FU in the small intestine
under the action of TP which is a tumour-
associated angiogenesis factor