Mutual prodrugs

The stability of some prodrugs and mutual prodrugs (8.137 and 8.139, Fig. 13) in human and rat plasma was also examined [175], An approximately tenfold acceleration was noted for the mutual prodrug 8.139 at pH 7.4 and 37° for human plasma (71/2 ca. 45 s) compared to buffer (t1/2 ca. 400 s). This and other evidence indicated that cleavage of these carbamates is enzymatic. In contrast, the A-(2-hydroxyphenyl)carbamates (8.137, Fig. 13) showed two- to threefold increases in t1/2 values in human and rat plasma compared to buffer, indicating the absence of an enzymatic hydrolysis, and modest stabilization due to binding to plasma proteins. 

A. Vigroux, M. Bergon, C. Zedde, Cyclization-Activated Prodrugs A-(Substituted 2-Hydroxyphenyl and 2-Hydroxypropyl)carbamates Based on Ring-Opened Derivatives of Active Benzoxazolones and Oxazohdinones as Mutual Prodrugs of Acetaminophen , J. Med. Chem. 1995, 38, 3983-3994. 

Sulbactam is produced by Pfizer. The oral version of sulbactam in combination with ampicillin is called Unasyn Oral, which is the mutual prodrug sultamicillin. Two sulbactam parenteral products are sold, a combination product with ampicillin called Unasyn and a combination with cefoperazone called Sulperazon. In addition, sulbactam is sold alone for parenteral use with any 0-lactain antibiotic as Betainaze. 

Codrugs are also named mutual prodrugs. Their design consists of the linking, in a unique molecule, of at least two different synergistic drugs that are released in vivo at the desired site of action. An example is found in the association of L-dopa to the catechol 0-methyltransferase (COMT) inhibitor entacapone (Figure 36.24). ... 

Mutual prodrugs. Prodrugs that contain free radials with pharmacological activity, which are effective in terms of decreasing side effects such as mucous membrane stimulation. 

Fukuhara, A. Imai, T. Otagiri, M. Stereoselective disposition of flurbiprofen from a mutual prodrug with a histamine H2-antagonist to reduce gastrointestinal lesions in the rat. Chirality 1996, 8, 494-502. 

Fig. 6.10. Schematic representation of a selective delivery obtained by targeting a cell-specific peptidase, a) The drug itself permeates passively into all cells, and no selectivity is achieved. b) The target cells contain a specific enzyme, which activates the prodrug in situ, c) The target cells produce a specific enzyme, which activates the prodrug in their vicinity. Note that cases b and c are not mutually exclusive and may, in fact, occur simultaneously.

S.S. Dhaneshwar, N. Gairola, M. Kandpal, G. Vadnerkar, L. Bhatt, B. Rathi, and S.S. Kadam, Synthesis, kinetic studies and pharmacological evaluation of mutual azo prodrugs of 5-ami-nosalicylic acid for colon-specific drug delivery in inflammatory bowel disease, Eur. J. Med. Chem. 44 3922-3929, 2009. 

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