Human inhalation pharmacokinetics of 1,1,2-trichloro-1,2,2-trifluoroethane (FC113).

Seven male volunteers were exposed to atmospheric concentrations of either 1980, 4100 or 7630 mg m-3 1,1,2-trichloro-1,2,2-trifluoroethane (FC113) for 4 h. Blood and expired air samples were collected during the exposure period and for several days subsequently and analysed for FC113. Blood and breath concentrations of FC113 were related to the administered dose with some variation between individuals. The low blood/breath ratios measured are consistent with the low solubility of FC113 in blood. The absorption and elimination of FC113 can be described by a three-compartment model and the average half-lives of elimination of FC113 in breath were 0.22, 2.3 and 29 h. A pulmonary retention during the exposure period of 14% was measured but only 2.6 to 4.3% of the dose was recovered unchanged in breath after the exposure period, suggesting that FC113 could be metabolised following inhalation exposure. It is concluded that a practical method for biological monitoring during occupational exposure would be to measure end-tidal breath concentrations of FC113 in samples taken the morning after exposure. The predictive value of such a measurement can be improved if the results are normalised to the body fat content of individual workers which can be estimated from height and weight measurements.

Human pharmacokinetics of temocillin (BRL 17421) side chain epimers.

The pharmacokinetics of the side-chain epimers of temocillin were investigated in four healthy male subjects following a single iv dose of temocillin disodium (1 g pure free acid) containing 64.2% R-epimer. Plasma and urinary concentrations of the epimers were determined by hplc methods. The R-epimer was twice as rapidly cleared, had a 23% larger volume of distribution and a 60% shorter beta half-life than the S-epimer. Intermediate values were obtained for total temocillin (from hplc data). The differences in the pharmacokinetic properties of the epimers are most likely the result of different extents of plasma protein binding. In each plasma sample, the free fraction of the R-epimer was higher (up to two-fold) than that of the S-epimer. In a comparison of temocillin pharmacokinetic parameters derived from hplc and microbiological assay data, the values obtained from the latter analyses reflected most closely those for the R-epimer. Further indications that the R-epimer is more microbiologically active against Pseudomonas aeruginosa NCTC 10701 from other assessments of relative antibacterial activity are discussed.

Human pharmacokinetics and antimicrobial activities of the temocillin epimers.

The pharmacokinetics of the epimers of temocillin were investigated in 4 healthy male subjects following intravenous administration of 1g of temocillin disodium (free acid) which contains a R : S epimer ratio of approximately 65 : 35. The R epimer had a 2-fold greater total plasma clearance, a 23% larger volume of distribution and a shorter beta half-life than the S epimer. Intermediate values were obtained for total temocillin (R + S) from high pressure liquid chromatography (HPLC) data. In each plasma sample, the unbound fraction of the R epimer was generally 2-fold higher than that of the S epimer, which is suggested as the reason for the differences in the pharmacokinetic properties of the epimers. The temocillin pharmacokinetic parameters obtained from the microbiological assay data reflect most closely those for the R epimer derived from HPLC data. The resolved R epimer exhibited twice the potency of the S epimer against the microbiological assay organism Pseudomonas aeruginosa NCTC 10701. However, in tests for antibacterial susceptibility, for instance minimum inhibitory concentration (MIC) determinations involving prolonged incubation, there was little difference in the inhibitory activities of the resolved R and S epimers compared with temocillin (R + S), presumably as a consequence of the epimerization of the individual epimers. In contrast, in rapid tests for bactericidal activity, which minimise the effect of epimerization, the R epimer exhibited greater bactericidal activity than the S epimer.