Scheme 76. Interaction of a drug (D) with a ligand (L). The interaction can lead to either stabilization of the drug (kc < kf) or catalysis of its breakdown (k > kf).
The term [D-L] represents the concentration of the complex, D-L, [D]yis the concentration of free or uncomplexed drug, and [L], is the concentration of free ligand. In Scheme 76, k, represents the rate constant for the degradation of the drug in the absence of complexation, and k, is the rate constant for the degradation of the drug in its complexed form. As can be seen, the drug will be stabilized by the presence of L if kc < k,. The degree of stabilization will also depend on the relative amounts of free and complexed drug, which in turn depends on the concentrations of D and L and the magnitude of K. Conversely, if kc > k,, complex formation will result in acceleration of the degradation. Differing ligands (L) in a series can affect the degradation rate in two ways: first, by affecting the degree of complexation, as measured by K, and, second, by affecting kc.
Stabilization of esters such as benzocaine (Fig. 120), procaine, and tetracaine by complex formation with caffeine was reported in the 1950s.513-515 The stabilization of drugs by caffeine is thought to result from the formation of "stacking" complexes. Thus, attack by water or hydroxide ion on the ester bonds of benzocaine is hindered when the benzocaine molecules are sandwiched between caffeine molecules. Similar stabilization by caffeine has been reported for base-catalyzed degradation of riboflavin.516
Ampicillin, cephalexin, and bacampicillin are stabilized by complex formation with aldehydes such as benzaldehyde and furfural,517-522 altho ugh this stabilization involves reversible formation of covalent species. Even though these interactions involve covalent bond formation, they follow Scheme 76, because the covalent association and dissociation (defined by the equilibrium constant K) is fast relative to kc and k,. The greater stability of N-nitrosoureas in Tris buffers than in carbonate buffers has been ascribed to complex formation with tris(hydroxymethyl)aminomethane.523
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