Etsuko Miyamoto

Physiological pharmacokinetics of Mactam antibiotics: penicillin V distribution and elimination after intravenous administration in rats

To clarify the physiological action and behaviour of a drug in man and to establish a dose scheduling for therapeutics, conventional pharmacokinetics based on the curve fits of the time-course of a drug concentration in blood have been widely used. The two-compartment open model is generally used for 8-lactam antibiotics administered to man and other species (e.g. Dittert et a1 1970; review by Nightingale et a1 1975). However, due to the lack of anatomical or physiological meaning for transfer rate constants derived from this method, the time-course of antibiotic concentration in the particular target organ, under normal and diseased states, appears difficult to predict. The present communication describes the physiologically based pharmacokinetics for penicillin V to predict tissue concentrations in rats. This approach by physiological perfusion model has been used to describe the pharmacokinetics of several drugs (for examples, Bischoff & Dedrick 1968; Bischoff et a1 1971 ; Benowitz et a1 1974; Harrison & Gibaldi 1977; Tterlikkis et a1 1977) and has the intrinsic possibility of being scaled up for application to man from animal results. Scheme 1 represents the flow diagram of various compartments used in the present analysis. This model assumes that (1) each tissue acts as a well-stirred compartment, (2) the antibiotic distribution is limited by the blood flow rate, and (3) tissue-to-blood concentration ratio of penicillin V is independent of the antibiotic concentration. A typical mass balance equation is given for the total drug in the liver:

Chemical reactions involved in penicillin allergy: kinetics and mechanism of penicillin aminolysis

In view of the fundamental importance of the reaction of penicillins with amino groups of proteins to the penicillin allergy, the aminolysis of benzylpenicillin by various amines was kinetically investigated. The formation rate constants, kamide, of benzylpenicilloylamides were determined at 35°, 45° and 60° (μ = 0·5), and found to obey the general rate law: kamide = k1[amine] + k2[amine H+] [amine] + k3[amine]2 + k4[amine]aOH. All of the amines exhibited the unassisted nucleophilic rate constant, k1. The relative importance of the other kinetic terms depends on the basicity and the chemical structure of amines. The reaction mechanism of penicillin aminolysis was discussed. Brønsted relations for k1, k2 and k3, except for hydrazines, were satisfactory.

Chemical aspects of penicillin allergy: imidazole-catalysed penicilloylation

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Effect of surfactants on degradation of penicillins and cephalosporins in acidic medium

It is well recognized that the acid stability of penicillins and cephalosporins is a factor affecting their oral absorption. The susceptibility of penicillins to acidcatalysed degradation is attributed to the intramolecular attack of the side-chain amide carbonyl upon the 8-lactam moiety (for reviews, see Hou & Poole, 1971). The rate of cleavage of the 8-lactam largely depends on the polar nature of the side chain (Doyle, Nayler & others, 1961). We found that the acid degradation of penicillins was significantly affected in a variety of ways by the addition of surfactants. An anionic surfactant enhanced the rate, whereas both cationic and non-ionic surfactants markedly inhibited degradation, as the result of penicillin-micelle interactions. During the preparation of this communication a report of the catalytic effect of a cationic micelle on the degradation of cephalexin at neutral pH appeared (Yasuhara, Sat0 & others, 1977). The present paper describes surfactant effects on the degradation of 8-lactam antibiotics in acidic medium.