Quantitative precision and accuracy in capillary zone electrophoresis (CZE) with electrokinetic (EK) injection is drastically improved by using matrix-corrected peak area (COPA) combined with calibration by regression with one internal standard. COPA compensates for the differentially changing electrophoretic mobilities of analytes and internal standards in sample matrices differing in composition from the electrophoresis and/or calibration buffer. Intraassay precision and accuracy are improved by factors up to 12 and 6.5, respectively. For interassay conditions, the inaccuracy data are lowered from beyond 15% to significantly below 5% relative deviation from the nominal concentration value. The

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1 Three double-blind, randomized, placebo controlled, multiple oral dose studies in patients with mild to moderate hypertension were performed to study tolerability, pharmacodynamics and pharmacokinetics of remikiren. Doses of 100-800 mg remikiren or placebo were given over 8 days to altogether 144 patient volunteers. In some cases (n = 46) single i.v. doses of 100 mg were administered 4 h after the last oral dose. Plasma remikiren concentrations, plasma renin activity and immunoreactive renin concentrations were measured. Pharmacokinetic parameters were estimated using model independent techniques and the concentration-effect relationship was evaluated using population pharmacometric methods. 2 In most patients no distinct absorption and disposition phase could be identified, since plasma concentrations fluctuated widely over a period of approximately 10 h. Peak plasma concentrations (Cmax) were achieved within 0.25-2 h postdose. Mean Cmax values (on the first and last day of oral treatment) were in the magnitude of 4-6 ng ml-1 (200 mg), 23-27 ng ml-1 (300 mg), 65-83 ng ml-1 (600 mg) and 47-48 ng ml-1 (800 mg). Cmax and AUCO-t values were clearly different for different doses within single studies. Intersubject variability in pharmacokinetic parameters was much higher than intrasubject variability. No drug accumulation in plasma was apparent. 3 Inhibition of the angiotensin I production rate correlated well with plasma drug concentrations according to the Emax-model. An IC50 value of 0.5 ng ml-1 (0.8 nM)was estimated. No correlation between blood pressure changes on the last day of oral treatment and either plasma remikiren concentrations or plasma renin inhibition was found.

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