What are prodrugs?
Not all active pharmaceutical ingredients are directly active. Some must first be converted to the active substance by an enzymatic or non-enzymatic conversion step in the body. These are the so-called . The term was introduced by Adrien Albert in 1958. It is estimated that up to 10% of all active ingredients in commerce today are prodrugs.
Advantages of the prodrug concept
Numerous reasons exist why active ingredients are developed as prodrugs. This approach can be used to improve a poor taste (e.g., chloramphenicol) and to increase the solubility of a lipophilic substance (e.g., valganciclovir). A common reason for prodrug design is to improve absorption and bioavailability (e.g., enalapril). In addition, tissue-specific distribution can be increased, thus avoiding side effects (targeting). Many antiviral agents (e.g. nucleoside analogues) and cytostatic drugs (e.g. capecitabine) are only activated in the infected cells or cancer cells and thus exert their effects predominantly at the desired site. Thus, prodrugs can be used to influence physicochemical, organoleptic, pharmacokinetic, and pharmacodynamic properties of drugs.
Disadvantages of prodrugs
Prodrugs, which are activated by enzymes such as CYP450 isozymes, are prone to interindividual differences and drug-drug interactions. If an enzyme is not sufficiently active or is blocked by an inhibitor, the active drug cannot be formed to a sufficient extent and the desired effect does not occur.
Structural features
Prodrugs are often coupled to a so-called carrier, which is cleaved off in the organism. These are referred to as . Frequently, these are esters. The (bioprecursors) do not contain a carrier and are metabolized or conjugated directly. A rare special case is represented by the (Mutual Prodrugs), in which two active substances are bound to each other and each is both active substance and carrier (examples: sulfasalazine, latanoprostenbunod).
Case study valaciclovir
Valaciclovir is a carrier-bound valine ester prodrug of the antiviral aciclovir that is released by hydrolysis after absorption. Valaciclovir was developed with the aim of increasing the poor bioavailability of aciclovir and improving its water solubility. Interestingly, aciclovir itself is also a prodrug that is selectively activated in virus-infected cells to form aciclovir triphosphate. Thus, several advantages of the prodrug concept come into play here.
Examples
The table shows a small selection of prodrugs:
- Acemetacin
- Acetylsalicylic acid
- Aciclovir
- Adefovirdipivoxil
- Amifostine
- Brivudine
- Candesartancilexetil
- Carbimazole
- Capecitabine
- Cidofovir
- Clopidogrel
- Codeine
- Desogestrel
- Disulfiram
- Enalapril
- Estramustine phosphate
- Famciclovir
- Fingolimod
- Fosaprepitant
- Leflunomide
- Lymecycline
- Nabumetone
- Nepafenac
- Olmesartan medoxomil
- Olsalazine
- Oseltamivir
- Penciclovir
- Prednisone
- Oseltamivir
- Simvastatin
- Sulfasalazine
- Tibolone
- Valaciclovir
- Valganciclovir