Examples of the Prodrug Approach

There have been numerous examples of the application of the prodrug approach to improve the oral bioavailability of drugs subject to extensive presystemic metabolism, with varying degrees of success. Some selected examples of prodrugs and the results observed are summarized in Table 1 and are discussed below. Also included in Table 1 are some examples of peptides for which the prodrug approach was utilized to potentially improve oral or transmucosal delivery by reducing metabolic degradation. Structures of some of these prodrugs are shown in Figure 2.

Nalbuphine (1) is an opioid analgesic that has incomplete oral bioavailability in animals and humans due to presystemic metabolism. The route of presystemic metabolism is primarily conjugation on the phenolic hydroxyl group. Two prodrugs were identified that markedly improved oral bioavailability in preclinical studies, the acetylsalicylate (2) and anthranilate (3) esters. These were designed to protect the phenolic position from conjugation. Bioavailability in dogs was approximately 5-7% after oral 1, 17-24% after oral 2, and approximately 50% after oral 3 (Aungst et al., 1987). Furthermore, the plasma concentrations and AUC of conjugated nalbuphine were reduced in dogs after dosing with the prodrugs, making it clear that first-pass metabolism was reduced. In rats, oral bioavailabilities were 2.7% after 1, 3.9% after 2, and 5.1% after 3, so these prodrugs were significantly less effective in rats than in dogs with regard to absolute oral bioavailability. This same approach was applied to the structurally related opioid antagonist naltrexone, which is similarly subject to presystemic conjugation at the phenolic hydroxyl position. Bioavailability in dogs was increased 45-fold after oral administration of the anthranilate ester prodrug and 28-fold after the acetylsalicylate prodrug, whereas benzoate and pivalate esters


Presystemic Metabolism




Nalbuphine (1)

Conjugation at phenolic -OH

Acetylsalicylate (2), anthranilate (3) esters on phenolic -OH

Increased oral F <2-fold in rats, increased oral F 8fold in dogs, decreased AUC of congugated nalbuphine

Aungst et al. (1987)


Conjugation at phenolic -OH

Anthranilate and other esters on phenolic -OH

Anthranilate ester increased oral F 28-45-fold in dogs

Hussain et al. (1987)


Conjugation at phenolic -OH

Salicylate ester

Increased oral F 30-fold in dogs

Hussain and Shefter (1988)

Nalbuphine, naloxone, naltrexone

See above

N-oxide (4)

Increased oral F several fold in dogs

Boswell and Myers, (1985)

Estradiol (5)

Conjugation at phenolic -OH

Acetylsalicylate, anthranilate esters on phenolic -OH

Increased oral F in dogs 17-fold with acetylsalicylate and 5-fold with anthranilate

Hussain et al. (1988)


See above

O-saccharinyl-methyl ester

Increased oral F (bio-activity) 5-fold in rats

Patel et al. (1995)


See above

Sulfamates (6)

Increased systemic estrogenic activity

Elger et al. (1995)

Salicylamide (7)

Conjugation at phenolic -OH

N-morpholi-nomethyl (N-Mannich base) (8)

Increased oral F 2.3-fold in rabbits

D'Souza et al. (1986)

Dopamine (9)

Conjugation of catechol

N-(N-acetyl-L-methionyl)O,O-bis-carbonyl dopamine (10)

Increased oral F 4fold in dogs, reduced concentrations of dopamine sulfate and DOPAC

Murata et al. (1989)


Sulfate conjugation of catechol, decarboxylation

Succinimidoethyl (S) and pivaloy-loxyethyl (P) esters

Both (S) and (P) increased oral absorption, (S) may be primarily conjugated before hydrolysis, while (P) is hydrolyzed before conjugation

Vickers et al. (1978)


See above

Pivaloyloxyethyl ester

Increased % of dose excreted as methyldopa, decreased sulfation

Vickers et al. (1984)

Table 1. Examples of Prodrugs to Reduce Presystemic Metabolism


Presystemic Metabolism





Conjugation at phenolic -OH

Bis-dimethylcar-bamate ester

No significant increase in plasma conc. in humans

Holstein-Rathlou et al. (1986)


Glucuronidation on P -OH, hydroxy-lation

Hemisuccinate on P -OH

Increased plasma AUC 8-fold after oral dosing in dogs

Garceau et al. (1978)


See above

Acetate, hemisuc-cinate on P -OH

Both prodrugs increased propranolol AUC 2.5-fold in rats

Anderson et al. (1988)


See above

Alkyl esters on P -OH

Increased oral F 2-4-fold in dogs

Shameem et al. (1993)

Di- and tripeptides


N-a-hydroxyalky-lation of the peptide bond

Increased metabolic stability

Bundgaard and Rasmussen (1991)

Various peptides



Increased metabolic stability

Kahns and Bundgaard (1991)



Pivalate ester on tyrosine

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  • Principio Fiorentino
    What are prodrugs abd their examples ?
    2 years ago
  • v
    What are prodrugs in psychiatry examples?
    8 months ago
  • johanna
    What is a pro drug / examples?
    4 months ago

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