PRODRUG DELIVERY

Definition of prodrug:

A prodrug is a medication or form of medication that, after oral administration under goes metabolized and
converted into a pharmacologically active form of drug.

Or

A prodrug is a chemically modified inert drug precursor, which upon biotransformation liberates the
pharmacologically active parent compound.

Concept of prodrug delivery:

The term prodrug, introduced in 1958 by Adrien Albert. Prodrugs are often designed to
improve bioavailability of poorly absorbed drug. Through the concept of prodrug ADME (absorption,
distribution, metabolism and excretion) of a poorly absorbed drug can be modified successfully. It also
improve the selectivity of drug towards a specific cell or tissue, hence, can be effectively used in drug
targeting. Most of the limitations can be overcame by prodrug approach, but after overcoming the various
barriers, the prodrug should rapidly convert into active moiety after reaching the target site. The concept
mainly focused towards the design of an efficient, stable, safe and acceptable strategies to target a drug to its
site of action. The prodrug approach holds great potential to deliver drug by overcoming various physical,
chemical and social barriers.

Objectives of Prodrug Design:

1. Pharmaceutical Objectives:
a. To improve solubility, chemical stability, and organoleptic properties.
b. To decrease irritation and/or pain after local administration,
c. To reduce problems related with the pharmaceutical technology of the active agent.
2. Pharmacokinetic Objectives:
a. To improve absorption (oral and by non-oral routes).
b. To decrease presystemic metabolism to improve time profile.
c. To increase organ/ tissue-selective delivery of the active agent.
3. Pharmacodynamic Objectives:
a. To decrease toxicity and improve the drug concentration with in therapeutic index.
b. To design single chemical entities combining effectiveness of two drugs (co-drugs strategy)

Classification of Prodrug:

The conventional method used to classify prodrugs is based on derivatization and the type of carriers attached
to the drug. This method classifies prodrugs into two sub-major classes:
(1) Carrier-linked prodrugs, in which the promoiety is covalently linked to the active drug but it can be
easily cleaved by enzymes (such as an ester or labile amide) or nonenzymatically to provide the parent drug.
Ideally, the group removed is pharmacologically inactive, nontoxic, and non-immunogenic, while the
promoiety must be labile for in vivo efficient activation. Carrier-linked prodrugs can be further subdivided
into:

(a) Bipartite which is composed of one carrier (promoiety) attached directly to the drug

(b) Tripartite which utilizing a spacer or connect a group between the drug and a promoiety. In some cases
bipartite prodrug may be unstable due to inherent nature of the drug-promoiety linkage. This can be solved by
designing a tripartite prodrug.

(c) Mutual prodrugs, which are consisting of two drugs linked together.

(2) Bio precursors which are chemical entities that are metabolized into new compounds that may be active
or further metabolized to active metabolites (such as amine to aldehyde to carboxylic acid). In this prodrug
type there is no carrier but the compound should be readily metabolized to induce the necessary functional
groups. In addition, prodrugs can be classified based on cellular site of interconversion into the active drug
form.

Five types of reactions can be involved in bio-precursor activation :

1. Oxidative reaction, catalyzed by CYP450 such as

(i) O and N dealkylation; e.g (bio-precursor prodrug for alprazolam),
(ii) Oxidative deamination; e.g. (cyclophosphamide activation)
(iii) N-oxidation; e. g (procarbazine activation).

2. Reductive activation such as

(i) Disulfide reaction; e. g (activation of thiamine prodrug) and
(ii) Bio-reductive alkylation; e.g. (activation of anticancer antibiotic, mitomycin c).
3. Nucleotide activation.
4. Phosphorylation activation; e. g (antiviral drug, acyclovir activation).
5. Decarboxylation activation; e. g (Nabumetone).

The classification strategy includes two types:

Type I: includes prodrugs that are converted to active drug intracellularly (e.g. anti-viral nucleoside analogs,
and lipid lowering statins).

Type II: involves prodrugs that are converted extracellularly, especially in digestive fluids or in the systemic
circulation (e.g. etoposide phosphate, valganciclovir, fosamprenavir, antibody-directed/gene-directed enzyme
prodrugs (ADEP/GDEP) for chemotherapy).
 Both types are further subdivided into subtypes (Type IA, IB and Type IIA, IIB, and IIC) based on
whether or not the intracellular converting location is the site of therapeutic action, or whether the conversion
occurs in the gastrointestinal (GI) fluids or systemic circulation.

Mutual Prodrug : Mutual prodrugs are a type of carrier linked prodrugs by which two pharmacologically
active agents linked together to form a single molecule. Each of these drugs acts as a carrier for the other.
Mutual prodrugs approach offers an efficient tool for improving the clinical and therapeutic effectiveness of
a drug that is suffering from some undesirable properties hindering its clinical usefulness. A common example
of this approach is benorylate (Figure 8), by which aspirin linked covalently to paracetamol through an ester
linkage, which claims to have decreased gastric irritation with synergistic analgesic effect.

PRODRUG ACTIVATION:

Conversion of prodrugs into the active form occurs enzymatically or chemically. Numerous and most
commonly carrier linkage prodrugs are designed to be activated via esterases. A wide range of esterases
distributed throughout the body, differ in their substrate specificity. Examples of esterases found in the body
are acetyl cholin esterases, butyryl cholin esterases, carboxylesterases and arylesterases . Therefore, prodrug
approach can be employed to control the release of the active compound at a specific site. One of the most
important enzymes involved in ester bioactivation are carboxylesterases (CESs). These enzymes are a multi-
gene family whose genes are localized in the endoplasmic reticulum (ER) of several tissues. These enzymes
efficiently catalyze the hydrolysis of a variety of ester- and amide-containing prodrugs to the corresponding
free acids. CESs show ubiquitous tissue expression profiles with the highest levels of CESs activity present in
the liver microsomal site. Hence the potential for their substrates to become involved in drug-drug interactions
is generally considered to be negligible. Examples of prodrug hydrolyzed by this type of esterases are enalapril
and pivampicillin
Application of Prodrug delivery:

1. Masking Taste and Odour: the Undesirable taste arises due to adequate solubility and interaction of
drug with taste receptors. It can be solved by lowering the solubility of drug using prodrug form.
Eg: chloramphenicol palmitate is the sparingly soluble of prodrug of chloramphenicol, which is
practically tasteless due to its low aqueous solubility, as well as it is hydrolysed to active
chloramphenicol by the action of pancreatic lipase.
2. Reduction of gastric irritation: it is effectively reduce the gastric irritation of drugs and improve the
patients comfort and acceptability towards the medicine.
Eg: Aspirin is a prodrug of salicylic acid is designed to reduce gastric irritation
3. Reduction in Pain at Site of Injection: The Pain caused by intramuscular injection is mainly due to
the weakly acidic nature or poor aqueous solubility of drugs. Through this prodrug concept it can be
minimize.
Eg: IM injection of antibiotics like clindamycin and anti convulsant like phenytoin was found to be
painful due to poor solubility. So, prodrugs are produced like 2’phosphate ester of clindamycin and
hydantoic ester prodrug of phenytoin (fosphenytoin) an aqueous soluble form of phenytoin
respectively
4. Enhancement of drug solubility and dissolution rate: The prodrug approach can be used to increase
or decrease the solubility of a drug, depending on its ultimate use. Therefore, it may be stated that the
drug dissolution rate can also be altered using prodrug concept. The prodrug approach is also made
useful for better gastrointestinal absorption.
Eg: Chloramphenicol succinate and chloramphenicol palmitate, ester prodrugs of chloramphenicol,
have enhanced and reduced aqueous solubility respectively. On the basis of altered solubility,
chloramphenicol sodium succinate prodrug is found suitable for parenteral administration.
5. Enhancement of chemical stability : Chemical stability is an important parameter for every
therapeutic agent. The prodrug approach mainly worked is based on the chemical modification of the
functional group responsible for the instability or by modification of physical properties of the drug
resulting in the reduction of contact between the drug and the media in which it is unstable.
6. Improvement of Bioavailablity: the prodrug concept successfully improve the bioavailability of
drug. As the concept is capable to improve the solubility by chemical and physical modification and
also efficiently improve the absorption of drug, therefore, bioavailability is also get improved. Again
the through the prodrug concept we can also able to convert the hydrophilic molecule into hydrophobic
one.
Eg. Dopamine was made useful by making its precursor L-Dopa. Though LDopa is highly polar, it is
actively transported through specific L–amino acid active transport mechanism and regenerates
dopamine by decarboxylation.
7. Prevention of Presystemic metabolism: All the orally administered drug must pass through two
metabolizing organs i.e., liver and gastrointestinal mucosa, before reaching the blood circulation. Two
types of drugs comes under this category. First, drugs those are rapidly degraded by the acid condition
and second Drugs that are degrade due to enzymes present in the gastrointestinal mucosa and liver.
Prodrugs may protect a drug from presystemic metabolism.
Eg. Naltrexone (treatment of opioid addiction) and is readily absorbed from GIT and hence undergoes
Presystemic metabolism. Ester prodrugs such as Onitrobenzoate and acetylsalicylate increased
bioavilablity 45 and 28 fold respectively.
8. Prolongation of duration of action: Drugs with short half-life require frequent dosing with
conventional dosage forms to maintain adequate plasma concentration. Prolongation of duration of
action of a drug can be accomplished by the prodrug.
9. Reduction Local and Systemic Toxicity of Drugs: Both local and systemic side effects can be
minimize through the prodrug concept.
Eg. Ibuterol is iisobutyrate ester of Terbutaline has longer duration of action and is free from both
local and systemic toxicity
10. Site specific drug delivery: this concept may also effectively serve the purpose of site specific drug
delivery or targeted delivery of drugs. The prodrug is converted into its active form only in the target
organ/tissue by utilizing either specific enzymes or a pH value different from the normal pH for
activation.

Conclusion:

Prodrug design is a part of the general drug discovery process, in which a unique combination of
therapeutically active substances is observed to have desirable pharmacological effects. In human therapy
prodrug designing has given successful results in overcoming undesirable properties like absorption, non-
specificity, and poor bioavailability and GI toxicity. Thus, prodrug approach offers a wide range of options
in drug design and delivery for improving the clinical and therapeutic effectiveness of drug.