Tsukinaka Yamana

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:

Saturable absorption of amino‐cephalosporins by the rat intestine

We have previously presented kinetic evidence indicating the existence of an interrelationship between concentration and in situ absorption of amoxicillin and cyclacillin by rat intestine (Tsuji et al 1977, 1978) and proposed that some types of carrier-mediated kinetics underlie the absorption mechanisms. In the present communication we report new findings indicating that in vivo absorption of amino-cephalosporins by rat intestine is governed by saturable kinetics in a manner similar to that of amino-penicillins. Cephalexin monohydrate and cephradine monohydrate were kindly supplied by Shionogi & Co., Osaka, Japan and Sankyo Co., Tokyo, Japan, respectively. Experimental conditions and in situ loop and recirculating perfusion methods were described previously (Tsuji et al 1977). Disappearance of antibiotics from the intestine was calculated from the amount of residual amino-cephalosporin assayed by high-pressure liquid chromatography (h.p.1.c.) as follows: A Model FLC A-700 equipped with a Model UVIDEC 100 ultraviolet detector set at 254 nm (Japan Spectroscopic Co., Tokyo, Japan) and a reversed phase column (SC-02, Japan Spectroscopic Co.) were used. The carrier was 7% acetonitrile-93% 001 M ammonium acetate. 50 pl of an appropriately diluted solution was injected through a variable loop-injector on flow, and peak

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.

Kinetics of Michaelis-Menten absorption of amino-penicillins in rats

Much interest has been focused on the absorption mechanism of amino-penicillins such as ampicillin, amoxicillin, and cyclacillin and amino-cephalosporins such as cephalexin and cephradine. Recent findings suggested that the intestinal absorption of amoxicillin in rats is governed by simple diffusion following firstorder kinetics a t high dose and is favoured by a specialized transport process following Michaelis-Menten kinetics a t low doses (Tsuji, Nakashima & others, 1977). The present communication describes the kinetic evidence for the Michaelis-Menten absorption of cyclacillin which has been recognized to be completely and rapidly absorbed after oral administration both in man and in animals (Warren, 1976). Cyclacillin anhydrate was kindly supplied from Takeda Chemical & Ind. Co. Ltd., Japan. The experimental conditions and the procedures for the in situ loop and recirculating perfusion methods were as described previously (Tsuji & others, 1977). Cyclacillin was assayed by the imidazole method (Bundgaard & Ilver, 1972) after the acylation of the amino group with acetic anhydride at p H 9 for the loop samples. The aliquots, 10-50 PI, of the sample withdrawn periodically from the recirculating perfusion solutions were analysed both by high-pressure liquid chromatography (h.p.1.c.) using a cation-exchange chromatomode and by microbiological assay (paper disk diffusion method) employing Surcina lutea. The conditions used for h.p.1.c. were as follows: instrument, JASCO FLC A-700 equipped with a variable wavelength ultraviolet detector setting at 210 nm, Model UVIDEC-100; column, Zipax SCX, Dupont; carrier, 0.1 M phosphate buffer of p H 4. The values from these three different analytical methods were confirmed to be in good agreement within the experimental errors. The % absorption of cyclacillin over 1 h from the in situ intestinal loop is presented in Fig. 1. The results indicate the marked difference in the extent of absorption depending upon the initial dose. At a low concentration (2 mg ml-l), cyclacillin was well absorbed (ca 80%) from every segment of the rat intestine, while a t high concentration (20 mgml-l), it was poorly absorbed (ca 18%), the difference being statistically highly significant ( P < 0401). The intermediate absorption (42-53 %) was observed a t 5 mg ml-l. There

Physiologically based pharmacokinetics of valproic acid in rabbits

Abstract Protein-binding parameters of valproic acid (VPA) in rabbit serum were determined. Due to the non-linear binding, the binding percentage decreased from 91 to 41% when the serum concentration of VPA rose from 10 to 1000 μg/ml. The hepatic clearance of VPA as unbound drug followed Michaelis-Menten kinetics. A physiologically based pharmacokinetics model was adopted to interpret the overall disposition of VPA in rabbits which incorporated the non-linear plasma protein binding and non-linear intrinsic hepatic clearance. The predicted plasma and tissue concentrations were found to be in good agreement with the observed concentrations. The reason why the plasma concentration versus time curves appear to be apparently parallel in spite of remarkable changes in the unbound concentration among three different doses could be explained by the association effects in which an increase in the total plasma concentration may produce a decrease in intrinsic hepatic clearance consistent with Michaelis-Menten kinetics resulting in an increase in the unbound fraction of VPA in plasma.

Chemical aspects of penicillin allergy: imidazole-catalysed penicilloylation

ALBERT, A. (1952). ALBERT, A. (1956). Ibid., 177, 403. BARRY, B. W. & BRAYBROOKS, H. P. (1974). BRAUN, R. J. & PARROTT, E. L. (1972). CURT, J. R. N. & PRINGLE, R. (1969). Gut, 10, 931-934. DEMAN, J., MAREEL, M. & BRUYNEEL, E. (1973). Biochem. Biophys. Acta, 297, 486-490. FLORENCE, A. T., ELWORTHY, P. H. & RAHMAN, A. (1973). J. Pharm. Pharmac., 25,779-786. JANOWITZ, H. D. & HOLLANDER, F. (1954). KELLAWAY, I. W. & MARRIOTT C. (1973). J. Pharm. Pharmac., 25, 167P-168P. LAWSON. D. (1967). MARRIOTT, C. & KELLAWAY, I. W. (1975). Biorheol., in the press. SAGGERS, B. & LAWSON, D. (1966). J. clin. Path., 19, 313-317. Nature (Lond.), 172, 201.

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.