1. 3 The Approach to Prodrug Concept & Classification Mohammed N. Sabir
Prodrug Approach – Fifth Year Lecture 1
Mohammed N. Sabir
Feb 2019 3
The Approach
to Prodrug Concept & Classification
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Prodrug Approach

2. What are the phases of drug actions???
Prodrug Approach – Fifth Year Lecture 1
What are the phases of drug actions???
A drug can only exert a desired pharmacological effect if it reaches its site of action. The three major phases involved in the drug receptor interaction or biological bioavailability of drug includes the pharmaceutical phase, the pharmacokinetic phase and pharmacodynamic phase 10. Many barriers which limit drug‟s ability to reach a desired target organ and the subsequent receptor site are considered of pharmacokinetic origin as shown in Fig 1.2.
Besides these, barriers of non-pharmacokinetic and pharmacodynamic origin may also prevent a drug from reaching the desired target. It includes pathological limitation such as toxicity, high incidence of side effects and teratogenicity, pharmaceutical limitation such as chemical instability of product or formulation, psychological limitation such as unpleasant taste, pain at injection site and cosmetic damage to the patient and economic barriers.
The awareness that the onset, intensity and duration of drug action are greatly affected by the physicochemical properties of drug has promoted the emergence of various theoretical and predictive models for drug design and evaluation 11, 12. The design of an efficient, stable, safe, acceptable and aesthetic way to target a drug to its site of action while overcoming Drug Tissue compartment Dosage form Deep compartment Control compartment Elimination product Target organ various physical, chemical and social barriers is certainly an area where the utilization of the prodrug approach holds great potential.
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3. Pharmacokinetic phase Pharmacodynamic phase
Prodrug Approach – Fifth Year Lecture 1
Pharmaceutical phase
Pharmacokinetic phase
Pharmacodynamic phase
The pharmaceutical phase can be considered as the phase of development which involves the identification of a new chemical entity with measured or proposed therapeutic potential and its incorporation into a drug delivery system. The delivery system may be one of the traditional forms such as tablet, capsules, injection and creams/ointment as well as the new drug delivery modes like loposomes, implants etc. Two barriers identified in the development phase of commercially usable drug products are:
(i) Aesthetic properties such as odour, taste (in case of pediatric use or when intended for oral administration), pain upon injection, gastrointestinal (GI) irritability of the new molecule.
(ii) Drug formulation problems. viz., stability profile, undesirable physicochemical properties like solubility, polarity, partition coefficient and PKa values due to which precludes its incorporation into a specific drug delivery system.
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Prodrug Approach

4. How to avoid pharmaceutical barriers?
Prodrug Approach – Fifth Year Lecture 1
How to avoid pharmaceutical barriers?
The use of Prodrugs (PD) to overcome pharmaceutical BARRIERS
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5. Lecture outlines… Definition and background What is meant by PD?
Prodrug Approach – Fifth Year Lecture 1
Lecture outlines…
Definition and background
What is meant by PD?
Why PD?
Barriers interfering drug action
How PD works?
Classification
Future prospects
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6. Prodrug Approach – Fifth Year Lecture 1
Definition…
Inactive derivatives of pharmacological active drugs that requires chemical or enzymatic transformation in biologic system to release the parent drug.
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7. Prodrug Approach – Fifth Year Lecture 1
It is designed to maximize efficacy through changing physicochemical, biopharmaceutical or pharmacokinetic properties, [Hu, 2004]
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8. Prodrug Approach – Fifth Year Lecture 1
Proagents [Albert, 1958]
“A pharmacologically inactive compound that is transformed by the mammalian system into an active substance chemically or by metabolic means”.
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9. Prodrug Approach – Fifth Year Lecture 1
Drug latentiation has been extended to include enzymatic and non-enzymatic regeneration of parent compound.
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10. Prodrug Approach – Fifth Year Lecture 1
So PD is a chemical entity undergoes chemical, physical or biological changes to overcome undesirable physicochemical properties, i.e.:-
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11. Prodrug Approach – Fifth Year Lecture 1
These changes improve delivery and targeting when compared to parent drug.
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12. 1. Improve activity WHY PDs ??? 2. Improve systemic disposition
Prodrug Approach – Fifth Year Lecture 1
WHY PDs ???
1. Improve activity
2. Improve systemic disposition
3. Decrease toxicities
4. Retain the desirable properties
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13. 5. Improve targeting (site selective drug delivery)
Prodrug Approach – Fifth Year Lecture 1
5. Improve targeting (site selective drug
delivery)
6. Modulate enzymatic activation
7. Improve acceptance by patients
8. Chemical stability
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14. 9. Prevention of pre-systemic drug metabolism
Prodrug Approach – Fifth Year Lecture 1
9. Prevention of pre-systemic drug
metabolism
10. Improve limited drug absorption and
distribution
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15. 11. Improve drug solubility. 12. Inadequate brain penetration.
Prodrug Approach – Fifth Year Lecture 1
11. Improve drug solubility.
12. Inadequate brain penetration.
13. local irritation toxicity.
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16. PD concept is now implemented in drug development.
Prodrug Approach – Fifth Year Lecture 1
PD concept is now implemented in drug development.
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17. Prodrug Approach – Fifth Year Lecture 1
Background…
The term was introduced by [Adrian Albert in 1958]
“A pharmacologically inactive compound that is transformed by the mammalian system into an active substance by their chemical metabolic means”
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18. Prodrug Approach – Fifth Year Lecture 1
The concept…
A PD is designed so that it can pass the barriers that the parent compound cannot.
Once it overcome these barriers, the parent compound will be released and exert activity.
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19. Promoiety helps to penetrate the biologic system
Prodrug Approach – Fifth Year Lecture 1
Drug
Promoiety
Biologic system
Biologic barrier
Promoiety helps to penetrate the biologic system
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20. 1- Designed to undergo biotransformation to active substance
Prodrug Approach – Fifth Year Lecture 1
PDs are either:-
1- Designed to undergo biotransformation to active substance
2- They do so originally
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21. Drug latentiation [Harper, 1959]
Prodrug Approach – Fifth Year Lecture 1
Drug latentiation [Harper, 1959]
Drugs specifically require bioactivation
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22. Soft and hard drugs… Prodrug Approach – Fifth Year Lecture 1 4/29/2019

23. Advantages and disadvantages of Hard and Soft drugs…
Prodrug Approach – Fifth Year Lecture 1
Advantages and disadvantages of Hard and Soft drugs…
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24. biotransformation Hard drug No toxic metabolite Soft drug
Prodrug Approach – Fifth Year Lecture 1
biotransformation
Hard drug
No toxic metabolite
Soft drug
Inert metabolite
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25. Challenges arise during drug development and formulations…
Prodrug Approach – Fifth Year Lecture 1
Challenges arise during drug development and formulations…
Partition coefficient optimization
Drug disposition in biologic system
Drug delivery
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26. Challenges arise during drug development and formulations…
Prodrug Approach – Fifth Year Lecture 1
Challenges arise during drug development and formulations…
Efficacy
Clinical toxicities
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27. Prodrug Approach – Fifth Year Lecture 1
“PD design can be very effective in solving many of the stability, solubility, permeability and targeting problems” [Hu, 2004],
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28. Parent drug + Inert carrier “pro-moiety”
Prodrug Approach – Fifth Year Lecture 1
Parent drug + Inert carrier “pro-moiety”
Biologic membrane (barrier)
Drug PD
Parent drug
Inert carrier +
A PD is a chemically modified inert drug precursor, which upon biotransformation liberate the pharmacologically active parent compound
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29. Prodrug Approach – Fifth Year Lecture 1
“In 2002, 14% of all new approved chemical drugs were PD” [Patil & Shirote, 2011]
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30. Prodrug Approach – Fifth Year Lecture 1
PD is a powerful approach to drug design that can target a wide range of drug molecules and different routs of administration.
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31. Prodrug Approach – Fifth Year Lecture 1
A comprehensive knowledge on the parent-drug physicochemical properties and the proper identification of barriers is crucial.
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32. Prodrug Approach – Fifth Year Lecture 1
PDs became a powerful tool for optimization of biologically active molecules through changing undesirable physicochemical, pharmaceutical and biopharmaceutical properties.
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33. PD properties… [Rautino et al, 2008]
Prodrug Approach – Fifth Year Lecture 1
PD properties… [Rautino et al, 2008]
Able to cross biologic barriers
To be cleaved efficiently through enzymatic or non-enzymatic reactions.
Rapid elimination of the pro-moiety
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34. New areas for application of PDs… Site-specific activation
Prodrug Approach – Fifth Year Lecture 1
New areas for application of PDs…
Site-specific activation
Delivery of anticancers to tumor tissues through transporters, tumor- or tissue-specific enzymes
Gene therapy
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35. PD concept strategies…
Prodrug Approach – Fifth Year Lecture 1
PD concept strategies…
To prepare a successful PD we need to understand the followings…
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36. 2- The target site of action
Prodrug Approach – Fifth Year Lecture 1
1- The physicochemical properties of the parent drug including its most active functional groups
2- The target site of action
3- The properties of the biologic barriers
4- The nature of the enzymatic biotransformation process
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37. Advantages of PD… [Smith and Clark] Increase absorption
Prodrug Approach – Fifth Year Lecture 1
Advantages of PD… [Smith and Clark]
Increase absorption
Alleviation of pain
Elimination of unpleasant taste
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38. Advantages of PD…[Smith and Clark] Decrease toxicity
Prodrug Approach – Fifth Year Lecture 1
Advantages of PD…[Smith and Clark]
Decrease toxicity
Decrease metabolic inactivation
Increased chemical stability
Prolonged or shortened action
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39. Hydrolysis of chloramphenicol succinate a PD
Prodrug Approach – Fifth Year Lecture 1
Hydrolysis of chloramphenicol succinate a PD
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40. Hydrolysis of chloramphenicol palmitate A PD
Prodrug Approach – Fifth Year Lecture 1
Hydrolysis of chloramphenicol palmitate A PD
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41. Pro-moieties should be eliminated directly and to be non-toxic
Prodrug Approach – Fifth Year Lecture 1
Pro-moieties should be eliminated directly and to be non-toxic
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42. Types of barriers in which PD may provide valuable help to overcome…
Prodrug Approach – Fifth Year Lecture 1
Types of barriers in which PD may provide valuable help to overcome…
Physicochemical barriers
1. Poor aqueous solubility – which prevent the drug from administrated in injectable form.
2. Low lipophilicity- which limits lipid bond formulation.
3. Chemical instability- which prevent the drug to incorporate into adequate forms.
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43. B. Barriers in the pharmacokinetic phase
Prodrug Approach – Fifth Year Lecture 1
B. Barriers in the pharmacokinetic phase
1. Incomplete absorption across biological membrane such as GIT mucosa & BBB.
2. Low & variable bioavailability due to extensive First pass effect.
3. Too rapid absorption or excretion when longer duration of the action is desired.
4. Lack of site specificity.
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44. Classification of PDs… Carrier linked PD Bioprecursors
Prodrug Approach – Fifth Year Lecture 1
Classification of PDs…
Carrier linked PD
Bioprecursors
Double PD pro-PD or cascade-latentiated PD
Macromolecular PD
Site- specific PD
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45. Classification of PDs… Carrier linked PD Bipartite PD Tripartite PD
Prodrug Approach – Fifth Year Lecture 1
Classification of PDs…
Carrier linked PD
Bipartite PD
Tripartite PD
Mutual PD
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46. Carrier linked PD specifications:
Prodrug Approach – Fifth Year Lecture 1
Carrier linked PD specifications:
Linked to an easily eliminated group (e.g. ester or amide)
The pro-moiety is linked to the parent drug by a labile to in vivo activation bond (mostly covalent)
The pro-moiety is pharmacologically inactive and non-toxic
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47. Carrier linked PD specifications:
Prodrug Approach – Fifth Year Lecture 1
Carrier linked PD specifications:
Such PD have greatly modified lipophilicity due to the attached carrier.
The active drug is released by hydrolytic cleavage either chemically or enzymatically.
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48. Inactive Easy breakable bonds Prodrug Approach – Fifth Year Lecture 1
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49. Active drug Covalent bond Inert carrier Chemical PD formation
Prodrug Approach – Fifth Year Lecture 1
Active drug
Inert carrier
Chemical PD formation
Chemical/enzymatic cleavage in vivo
Covalent bond
Patil & Shirote, 2011, IJMPS,
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50. Prodrug Approach – Fifth Year Lecture 1
1. Bipartite PDs
Composed of one carrier group attached to parent drug through covalent bond
The carrier act as transport molecule (modulate the lipophilicity/ hydrophilicity ratio)
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51. Prodrug Approach – Fifth Year Lecture 1
1. Bipartite PDs
The active drug is released by hydrolytic cleavage (chemically or enzymatically)
- Both drug and carrier should be non-toxic after releasing in vivo
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52. Prodrug Approach – Fifth Year Lecture 1
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53. Patil & Shirote, 2011, IJMPS, www.ijmps.com
Prodrug Approach – Fifth Year Lecture 1
2. Tripartite PDs
Composed of the Drug attached to Carrier group via linker
Drug
Linker
Carrier
Patil & Shirote, 2011, IJMPS,
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54. Bacampicillin a PD for ampicillin
Prodrug Approach – Fifth Year Lecture 1
Carrier
Linker
Bacampicillin a PD for ampicillin
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55. Prodrug Approach – Fifth Year Lecture 1
3. Mutual PDs
Composed of two pharmacologically active agents coupled together so that each acts as a pro-moiety for the other agent.
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56. Prodrug Approach – Fifth Year Lecture 1
A mutual PD could be bi- and tripartite PD in which the carrier is a synergistic drug with the drug which is linked.
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57. Patil & Shirote, 2011, IJMPS, www.ijmps.com
Prodrug Approach – Fifth Year Lecture 1
Patil & Shirote, 2011, IJMPS,
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58. Prodrug Approach – Fifth Year Lecture 1
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59. Esterases - Ampicillin -Penicillanic acid - Sulfone - Formaldehyde
Prodrug Approach – Fifth Year Lecture 1
Esterases
- Ampicillin
-Penicillanic acid
- Sulfone
- Formaldehyde
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60. Prodrug Approach – Fifth Year Lecture 1
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61. Prodrug Approach – Fifth Year Lecture 1
Problems with high lipophilicity of estradiol can also be solved by phosphorylation or linking to carbamate group, this give the drug more bioavailability…
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62. B. Double PD pro-PD or cascade-latentiated PD
Prodrug Approach – Fifth Year Lecture 1
B. Double PD pro-PD or cascade-latentiated PD
where a PD is further derivatized in a fashion such that only enzymatic conversion PD is possible before the latter can cleave to release the active drug.
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63. Prodrug Approach – Fifth Year Lecture 1
C. Macromolecular PD
where macromolecules like polysaccharides, dextrans, cyclodextrins, proteins, peptides and polymers are used as carriers.
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64. Prodrug Approach – Fifth Year Lecture 1
D. Site- specific PD
where a carrier acts as a transporter of the active drug to a specific targeted site.
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65. Prodrug Approach – Fifth Year Lecture 1
Bioprecursors…
These do not linked to carriers, but rather need latentiation which is metabolically activated.
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66. These bioactivation (enzymatic activation) rely on:-
Prodrug Approach – Fifth Year Lecture 1
These bioactivation (enzymatic activation) rely on:-
Reductive activation
Oxidative activation
Rather than hydrolytic reactions
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67. Prodrug Approach – Fifth Year Lecture 1
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68. Prodrug Approach – Fifth Year Lecture 1
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69. Prodrug Approach – Fifth Year Lecture 1
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70. Prodrug Approach – Fifth Year Lecture 1
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71. Novel Classification 1- Type I PD 2- Type II PD
Prodrug Approach – Fifth Year Lecture 1
Novel Classification
1- Type I PD
2- Type II PD
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72. • Type I PD are bioactivated inside the cells (intracellularly).
Prodrug Approach – Fifth Year Lecture 1
• Type I PD are bioactivated inside the cells (intracellularly).
Ex.,
Anti-viral nucleoside analogs that must be phosphorylated and the lipid-lowering statins.
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73. Prodrug Approach – Fifth Year Lecture 1
• Type II PD are bioactivated outside cells (extracellularly), especially in digestive fluids or in the body's circulation system,
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74. mercaptopurine, mitomycin, zidovudine
Prodrug Approach – Fifth Year Lecture 1
Type
Bioactivation site
Subtype
Tissue location of
bioactivation
Examples
Type I
Intracellular
Type IA
Therapeutic target
tissues/cells
Aciclovir, fluorouracil, cyclophosphamide, diethylstilbestrol diphosphate, LDOPA,
mercaptopurine, mitomycin, zidovudine
Type IB
Metabolic tissues (liver, GI
mucosal cell, lung etc.)
Carbamazepine, captopril, carisoprodol,
heroin, molsidomine, leflunomide, paliperidone, phenacetin, primidone, psilocybin, sulindac, fursultiamine, codeine
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
ADEPTs, GDEPs, VDEPs
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75. PDs for Site Selective Drug Delivery (SSDD)
Prodrug Approach – Fifth Year Lecture 1
PDs for Site Selective Drug Delivery (SSDD)
SSDD is the ultimate goal in drug therapy.
Site selectivity achieved by:-
Passive drug enrichment in the organ
Transporter mediated delivery
Selective metabolic activation through enzymes
Antigen targeting
e.g.; CNS, tumor and liver targeting
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76. PDs as an approach for drug targeting…
Prodrug Approach – Fifth Year Lecture 1
PDs as an approach for drug targeting…
Why Drug targeting?
Important strategies for targeting:-
Chemical delivery system (CDS)
Soft drug design
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77. Retrometabolic Drug Design (RMDD)…[Bodor and Buchwald,1997]
Prodrug Approach – Fifth Year Lecture 1
Retrometabolic Drug Design (RMDD)…[Bodor and Buchwald,1997]
-RMDD combines SAR & MAR
-Inclusion of metabolic consideration in drug design to approach safer drug (improved therapeutic index).
-RMDD utilizes both CDS & SDD
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78. Prodrug Approach – Fifth Year Lecture 1
RMDD design concept, (Bhardwaj et al, 2014), Saudi Pharmaceutical Journal (2014) 22, 290–302
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79. Prodrug Approach – Fifth Year Lecture 1
CDS is defined as metabolic activation of biologically inactive drugs through predicted enzymatic pathways to deliver the drug to the site of action.
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80. In CDs it is important to recognize the enzymes at the site of action.
Prodrug Approach – Fifth Year Lecture 1
In CDs it is important to recognize the enzymes at the site of action.
CDS concept has been applied in a variety of drug targeting strategies, achieving successful delivery to the brain, eye and other organs of the body
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81. Prodrug Approach – Fifth Year Lecture 1
Drug targeting through CDS requires enzymatic activation to yield the active drug.
The system should have a covalent link between the drug and carrier and one bond needs to be broken.
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82. 1- A target which is responsible for site specificity “targeting”
Prodrug Approach – Fifth Year Lecture 1
In CDS, the molecule is converted to inactive form by adding two moieties:-
1- A target which is responsible for site specificity “targeting”
2- A modifier (can be more than one) for the protection of certain functional groups and to prevent the drug from unwanted metabolic reactions
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83. Prodrug Approach – Fifth Year Lecture 1
Some examples on CDSs…
Progestin chemical delivery system 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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84. Lecture overview… Prodrug Approach – Fifth Year Lecture 1 4/29/2019

85. End of lecture… Any questions? Prodrug Approach – Fifth Year Lecture 1
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