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Notes: Summary Marked interindividual variation has been observed in the pharmacokinetics of the antiarrhythmic agent mexiletine. The fact that its urinary excretion is dependent on urinary pH may account, in part, for such variation. The influence that genetic differences in hepatic metabolism of the debrisoquine-type may have on mexiletine pharmacokinetics was considered in this study. The pharmacokinetics and urinary excretion of mexiletine (250 mg administered intravenously) were investigated in 5 rapid extensive metabolisers (EM), 5 slow EM and 5 poor metabolisers (PM) of debrisoquine, under conditions of controlled urinary pH. Mexiletine disposition kinetics was found to be altered in PM individuals. These subjects showed higher total area under the curve (AUC), (15.7 versus 8.16 μg · h · ml−1) prolonged elimination half-lives (in serum and urine) (serum: 18.5 versus 11.6 h, urine: 19.2 versus 11.7 h) and lower total clearance values compared with EM (216 versus 450 ml · min−1). In this respect, slow EM individuals generally presented intermediate values of those pharmacokinetic parameters. A higher incidence of adverse-effects was also observed among slow EM and PM subjects. It is concluded that genetic differences in mexiletine oxidation of the debrisoquine-type have an influence on its observed pharmacokinetic variability. The clinical consequences are discussed.

Notes: Abstract Photosynthesis was studied in four species of red marine macroalgae: Palmaria palmata, Laurencia pinnatifida, Lomentaria articulata and Delesseria sanguinea. The rate of O2 evolution for submersed photosynthesis was measured as a function of incident photon flux density at normal pH and inorganic carbon concentration (pH 8.0, 2 mol m−3), and as a function of inorganic carbon concentration at pH 8.0 at saturating and at limiting photon flux density. The rate of CO2 uptake was measured for emersed photosynthesis as a function of CO2 partial pressure at saturating photon flux density. Previous pH-drift results suggest that Palmaria and Laurencia are able to use HCO inf3 sup− as well as CO2 whereas Lomentaria and Delesseria are restricted to CO2. None of the algae are saturated by 2 mol m−3 inorganic carbon at high light (400 μmol m−2 s−1) but are saturated at low light (35 μmol m−2 s−1). The inorganic C concentration at which half the light-saturated rate of O2 evolution is achieved is higher for Palmaria and Laurencia (1.51 and 1.85 mol m−3) than for Lomentaria and Delesseria (0.772 and 0.841 mol m−3). The lower values for the latter two species could reflect their putative restriction to CO2. If expressed in terms of CO2, the half-saturation values yield 7.2 and 7.8 mmol m−3 respectively, which are very similar to values obtained previously during pH-drift experiments but at lower concentrations of HCO inf3 sup− , consistent with restriction to CO2. The photosynthetic conductance (m s−1), calculated from the initial slope for photosynthesis at low concentrations of inorganic carbon, correlates with the suggested ability to extract inorganic carbon based on pH-drift results. Calculations made assuming that CO2 is the only species diffusing across the boundary layer are consistent with boundary layer thicknesses of 20 and 19 μm for Lomentaria and Delesseria respectively, which is feasible given the rapid water movement in the experiments. For Laurencia however, an unreasonably small boundary layer thickness of 6 μm is necessary to explain the flux, which indicates co-diffusion by HCO inf3 sup− . In the apparent absence of external carbonic anhydrase, direct uptake of HCO inf3 sup− , rather than external conversion to CO2 is indicated in this species. In air, the CO2 concentration at which photosynthesis is half-maximal increases in the same order as the ability to raise pH in drift experiments. At 21 kPa the CO2 compensation partial pressures for Palmaria and Laurencia at 0.56 and 1.3 Pa are low enough to suggest a carbon-concentrating mechanism is operating, while those of Lomentaria at 1.8 Pa and particularly that of Delesseria at 4.5 Pa could be explained without a carbon-concentrating mechanism. The algae tested (all except Delesseria) showed more O2 evolution than could be accounted for with a photosynthetic quotient of 1.0 and uncatalysed conversion of HCO inf3 sup− to CO2 outside the cell in high light at pH 8.0 when high algal fresh weight per unit medium was used. These results are concordant with other data suggesting use of HCO inf3 sup− by Palmaria and Laurencia, but discordant with the rest of the available information in indicating use of HCO inf3 sup− by Lomentaria. The reason for this is unclear. The lightsaturated rate of O2 evolution on an algal area basis and the photon flux density needed to saturate photosynthesis were related partly to the habitat from which the seaweeds were collected, but more strongly to the ability to use HCO inf3 sup− . Values for the two users of HCO inf3 sup− , Palmaria (population used was intertidal; also occurs subtidally) and Laurencia (intertidal/shaded intertidal), were greater than for Lomentaria (shaded intertidal), which was greater than Delesseria (subtidal), both of which are believed to be restricted to CO2. In accordance with earlier δ13C data and, for Delesseria, estimates of the achieved growth rates in situ, carbon is likely to be saturating and use of HCO inf3 sup− is unlikely to occur in the normal low-light habitats of Lomentaria and Delesseria. Analysis of N-use efficiencies show that they are closer to the low-CO2-affinity Laminariales than the high-CO2-affinity Fucaceae.