CHEMICAL STUDIES OF POTENTIAL RELEVANCE TO PENICILLIN HYPERSENSITIVITY: KINETIC STUDIES OF METHICILLIN, PHENOXYMETHYLPENICILLIN AND THEIR PENICILLENIC ACIDS

¹ School of Medicine, University of North Carolina, Chapel Hill, North Carolina

Crystalline DL-(2,6-dimethoxyphenyl)penicillenic acid and crytalline DL-phenoxymethylpenicillenic acid, which are the respective isomers of methicillin and phenoxymethylpenicillin, were synthesized. Spectrophotometric kinetic studies were made in buffers of different pH values and phosphate concentrations at the absorption maxima, 330 nm for dimethoxyphenylpenicillenic acid and 322 nm for phenoxymethylpenicillenic acid. In dilute oxygen-free phosphate buffers, decrease of absorption of dimethoxyphenylpenicillenic acid with time is compatible with the mechanism previously postulated for benzylpenicillenic acid, viz., equilibration of the penicillenic acid with a nonabsorbing thiazolidinyl-oxazolone isomer and destruction of the latter through first-order reactions. Absorbancy of phenoxymethylpenicillenic acid as a function of time is more complex under some conditions, being compatible with a mechanism in which there is an additional equilibrium between the thiazolidinyl-oxazolone and another nonabsorbing compound. In the presence of oxygen, absorbancy in solutions of all the penicillenic acids plateaus at higher values than in the absence of oxygen, indicating oxidation of the sulfhydryl groups with formation of stable absorbing products. Ultraviolet absorption indicative of penicillenic acid formation develops in solutions of methicillin and phenoxymethylpenicillin. In the presence of oxygen, which traps the penicillenic acids in absorbing forms, this absorption is greater than in the absence of oxygen. The apparent rates of formation of penicillenic acid are comparable for methicillin and benzylpenicillin. For phenoxymethylpenicillin, the rate is much lower and is not augmented to the same extent by the hydrogen ion. With all the penicillins studied, the postulated thiazolidinyloxazolone isomers of the penicillinic acids could suffice to penicilloylate protein adequate to play at least some role in penicillin hypersensitivity phenomena.