1. Prodrug Approach – Fifth Year Lecture 2
Mohammed N. Sabir
March 2019 9
Prodrug Approach Classification, Chemical Delivery System & Drug Targeting
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2. Review of the last lecture
Prodrug Approach – Fifth Year Lecture 2
Lecture outlines…
Review of the last lecture
Novel classification system for Prodrugs (PDs)
Site selective drug delivery (SSDD)
Chemical delivery system (CDS) in drug targeting strategy (DTS)
Lecture overview
Discussion
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3. Prodrug Approach – Fifth Year Lecture 2
Some examples on CDSs…
Progestin CDS was developed to transport gonadal steroids like estradiol and testosterone to the CNS to avoid its peripheral untoward actions like hypertension and weight gain
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4. Prodrug Approach – Fifth Year Lecture 2
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5. Prodrug Approach – Fifth Year Lecture 2
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6. Classification of PDs based on regulatory perspectives
Prodrug Approach – Fifth Year Lecture 2
Classification of PDs based on regulatory perspectives
Classification based on regulatory metabolic patterns show risk-benefit assessment of PDs since more information about kinetics and impact of target and metabolic tissue are revealed.
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7. Prodrug Approach – Fifth Year Lecture 2
Drug-action analysis is based on site and mode of actions, hence the PD classification will be more expressive if based on the site where metabolic activation is achieved.
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8. Prodrug Approach – Fifth Year Lecture 2
A useful classification for PDs will be a risk-benefit assessment based on the site of action providing insight into the kinetics of the conversion process and contribution of the PD to the product’s safety and efficacy.
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9. Intracellular metabolic activation is needed Sub-classes:-
Prodrug Approach – Fifth Year Lecture 2
Type I PDs…
Intracellular metabolic activation is needed
Sub-classes:-
Type IA (e.g. antiviral nucleosides), activated in target cell.
Type IB (e.g. lipid lowering statins), activated in metabolic tissue like liver and lung.
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10. Extracellular metabolic activation is needed Sub-classes:-
Prodrug Approach – Fifth Year Lecture 2
Type II PDs…
Extracellular metabolic activation is needed
Sub-classes:-
Type IIA (e.g. etoposide phosphate), activated in digestive fluids.
Type IIB (e.g. valganciclovir), activated in systemic circulation.
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11. Prodrug Approach – Fifth Year Lecture 2
Type II PDs…
Type IIC (e.g. fosamprenavir, ADEPT, GDEPT. VDEPT), activated in the vicinity of the target cell.
This type relies on esterases, phosphatases or target directed enzyme.
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12. Tissue Location of Conversion
Prodrug Approach – Fifth Year Lecture 2
Classification of Prodrugs
Prodrug Types
Site of Conversion
Subtypes
Tissue Location of Conversion
Examples
Type I
Intracellular A
Therapeutic Target Tissues/Cells
Type IA:
Acyclovir
5-Flurouracil
Cyclophosphamide
Diethlstilbestrol diphosphate
L-Dopa
6-Mercaptopurine
Mitomycine C
Zidovudine B
Metabolic Tissues (liver, GI mucosal cell, lung, etc.)
Type IB:
Cabamazepine
Captopril
Carisoprodol
Heroin
Molsidomine
Paliperidone
Phenacetin
Primidone
Psilocybin
Suldinac
Tetrahydrofurfuryl disulfide
Table 1
Classification of Prodrugs
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13. Tissue Location of Conversion
Prodrug Approach – Fifth Year Lecture 2
Classification of Prodrugs
Prodrug Types
Site of Conversion
Subtypes
Tissue Location of Conversion
Examples
Type II
Extracellular A
GI Fluids
Type IIA:
Lisdexamfetamine
Loperamide oxide
Oxyphenisatin
Sulfasalazine B
Systemic Circulation and Other Extracellular Fluid Compartments
Type IIB:
Acetylsalicylate
Bacampicillin
Bambuterol
Chloramphenicol succinate
Dihydropyridine pralixoxime
Dipivefrin
Fosphenytoin C
Therapeutic Target Tissues/Cells
Type IIC:
ADEPs
GDEPs
VDEPs
Table 1
Classification of Prodrugs
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14. When a PD belongs to multiple categories…
Prodrug Approach – Fifth Year Lecture 2
Mixed-Type PDs…
When a PD belongs to multiple categories…
“Type IA/IB” PD, activated in both target cell and metabolic tissue (e.g. statins).
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15. Mixed types may be parallel “ / ” or sequential “ - ”.
Prodrug Approach – Fifth Year Lecture 2
Mixed-Type PDs…
Mixed types may be parallel “ / ” or sequential “ - ”.
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16. Prodrug Approach – Fifth Year Lecture 2
3- “Type IIA-IA” PD when PD converted sequentially, e.g., Tenofovir disoproxil fumarate.
Others like ADEPs, VDEPs, GDEPs, nanoparticle – or nanocarrier-linked drugs can be sequential Mixed-Type PDs.
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17. Strategic goals for improving PD design are:-
Prodrug Approach – Fifth Year Lecture 2
Strategic goals for improving PD design are:-
1- If the PD will be converted fast and completely into the parent drug.
2- If the PD contributes to the active drug’s toxicity profile.
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18. Rev., PDs designed when:-
Prodrug Approach – Fifth Year Lecture 2
Rev., PDs designed when:- #
Problem
Example 1
Bioavailability (poor water solubility)
Corticosteroids 2
Poor absorption/permeability
Ampicillin 3
High first pass metabolism
Propranolol 4
Instability (short ½ life)
Dopamine 5
Poor site specificity
Anticancers 6
Incomplete absorption
Epinephrine 7
Undesirable organoleptic properties
Chloramphenicol 8
Formulation difficulties
Erythromycin 9
Toxicities
Estradiol
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19. Prodrug Approach – Fifth Year Lecture 2
The major groups of carrier-linked prodrugs are esters and amides; other groups include phosphates, carbamates, carbonates, oximes, imines and N-Mannich bases
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20. Prodrug Approach – Fifth Year Lecture 2
Common functional groups on
parent drugs applied in prodrug design.
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21. Prodrug Approach – Fifth Year Lecture 2
Ester PDs of [-OH, -COOH & -SH] are the most common types of PDs (49%), modification via esters are made for enhancing lipophilicity.
Once penetrate biologic membranes undergo enzymatic hydrolysis by esterases in blood, liver and other organs by:-
-Carboxyl esterases
-Acetylcholinesterases
-Butyrylcholinesterases
-Paraoxonases
-Arylesterases.
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22. Prodrug Approach – Fifth Year Lecture 2
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23. Prodrug Approach – Fifth Year Lecture 2
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24. Carbonates and carbamates PDs, [-COOH, -OH or NH2]…
Prodrug Approach – Fifth Year Lecture 2
Carbonates and carbamates PDs, [-COOH, -OH or NH2]…
More stable to hydrolysis when compared to esters and less than amides.
Activated by the esterases.
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25. Prodrug Approach – Fifth Year Lecture 2
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26. Amides as PDs for [-COOH and –NH2]
Prodrug Approach – Fifth Year Lecture 2
Amides as PDs for [-COOH and –NH2]
Less applied because of high stability to hydrolysis.
Hydrolyzed in vivo by:-
-Carboxylesterases, peptidases or proteases.
Amides are applied to enhance absorption through specific intestinal uptake transporters.
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27. Prodrug Approach – Fifth Year Lecture 2
Human Carboxylesterase-2 Hydrolyzes the Prodrug of Gemcitabine (LY ) and Confers Prodrug Sensitivity to Cancer Cells [Pratt E., et al., 2013, Cl Ca Res.]
Gemcitabine inhibits thymidylate synthetase, leading to inhibition of DNA synthesis and cell death. Gemcitabine is a prodrug so activity occurs as a result of intracellular conversion to two active metabolites, gemcitabine diphosphate and gemcitabine triphosphate by deoxycitidine kinase. Gemcitabine diphosphate also inhibits ribonucleotide reductase, the enzyme responsible for catalyzing synthesis of deoxynucleoside triphosphates required for DNA synthesis. Finally, Gemcitabine triphosphate (diflurorodeoxycytidine triphosphate) competes with endogenous deoxynucleoside triphosphates for incorporation into DNA.
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28. Prodrug Approach – Fifth Year Lecture 2
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29. Prodrug Approach – Fifth Year Lecture 2
Ketone derivative including oximes (ketoximes, amidoximes and guanidoximes)
providing an
These functional groups modify compounds lacking [-OH. –NH2 or –COOH] and enhance membrane permeability.
They are hydrolyzed by cytochrome P450.
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30. [O] P450 Prodrug Approach – Fifth Year Lecture 2 4/11/2019

31. Lecture overview… Prodrug Approach – Fifth Year Lecture 2 4/11/2019

32. End of lecture… Thanks for paying attention Any questions?
Prodrug Approach – Fifth Year Lecture 2
End of lecture… Thanks for paying attention
Any questions?
4/11/2019
Prodrug Approach