TABLE 1

The rationale behind the use of the prodrug approach

Barrier to Overcome	Examples of Applicable Prodrugs	Preferable Site of Bioconversion	Common Functional Groups Amenable to the Prodrug Method
Formulation and administration	Introducing ionizable or polar neutral group	During or after absorption	-OH -SH -NH (via spacer) -COOH
Low aqueous solubility Low shelf-life Pain or irritation after local administration Unpleasant taste/odor	Phosphates Amino acid esters/amides Sugar derivatives	at the brush border of enterocytes in the systemic circulation or after local administration in the systemic circulation by hydrolytic enzymes	-OH -SH -NH (via spacer) -COOH
Absorption	Masking polar ionized/non-ionized group(s)	After absorption	-OH -SH -NH -COOH -OPO(OH)₂
Poor membrane permeation Low stability in GI tract Substrate of efflux transporters	Alkyl/aryl esters Amino acid esters/amides	in the systemic circulation by hydrolytic enzymes	-OH -SH -NH -COOH -OPO(OH)₂
Distribution	Targeting cell- or tissue-specific transporters or enzymes	In the target tissue	-OH -SH -NH -COOH
Lack of site specificity High degree of plasma protein binding	Amino acid esters/amides Sugar derivates	by cell-specific hydrolytic enzymes or oxidoreductases	-OH -SH -NH -COOH
Metabolism and excretion	Masking metabolically labile group(s) or polar ionized/nonionized group(s)	After absorption	-OH -SH -NH -COOH -OPO(OH)₂
Short duration of action	Alkyl/aryl esters Amino acid esters/amides	in the systemic circulation in the target tissue by hydrolytic enzymes	-OH -SH -NH -COOH -OPO(OH)₂
Toxicity	Targeting tissue-specific enzymes or divergent conditions of target tissue	In the target tissue	Depending on the selected prodrug method (these prodrugs are often bioprecursors)
Lack of site specificity	Various different prodrug methods	by cell-specific enzymes because of altered pH or hypoxia
Life-cycle management	Introducing any kind of promoiety	Depending on the selected prodrug method	Depending on the selected prodrug method (these prodrugs are often carrier-linked prodrugs)
	Various different prodrug methods	Depending on the selected prodrug method

GI, gastrointestinal.