In an open crossover study, the pharmacokinetics of three-day and five-day regimens of azithromycin were compared. Fourteen healthy volunteers received oral doses of azithromycin once-daily, over three days (500 mg/day) and over five days (500 mg on day 1, followed by 250 mg/day on days 2-5). Plasma and urine concentrations were determined by HPLC. Azithromycin was found to be absorbed rapidly on the first and the last days of both regimens, with mean Tmax ranging between 2.5-3 h. On day 1, peak plasma concentrations were 0.37 mg/L and 0.31 mg/L, respectively, with three- and five-day regimens, and increased to 0.42 mg/L on the last day of the three-day regimen, but decreased to 0.18 mg/L at the end of the five-day regimen. Similarly, the AUC0-24 increased from 1.30 to 1.88 h.mg/L during the three-day regimen, and decreased from 1.24 to 0.80 h.mg/L on the five-day regimen. After absorption, azithromycin was distributed rapidly; the respective half-lives were 2.4 h and 2.2 h with the three-day and five-day regimens. Thereafter, a polyphasic decline of plasma concentrations was observed; the average half-lives between 8-48 h after administration were 27.9 h (three-day regimen) and 35.8 h (five-day regimen). In urine, 5.5% (three-day regimen) and 4.6% (five-day regimen) of the total dose was found as unchanged azithromycin over a 12-day period. The observed pharmacokinetics of azithromycin with both regimens conformed with the known pharmacokinetic behaviour of the drug. The treatment-related differences seen in the plasma concentrations were as expected from the different dosage schedules.

Plasma concentrations of (R)- and (S)-amlodipine were measured after single oral administrations to 18 healthy volunteers of 20 mg amlodipine racemate. The contribution of the pharmacologically active (S)-enantiomer to the concentrations of total amlodipine (sum of enantiomers) was significantly higher than that of the inactive (R)-enantiomer, with mean values of 47% R to 53% S for the Cmax and 41% R to 59% S for the AUC (range between 24% R:76% S and 50% R:50% S). The oral clearance of the active (S)-form was subject to much less intersubject variation (25% CV) than that of the inactive (R)-form (52% CV). (R)-Amlodipine was more rapidly eliminated from plasma than (S)-amlodipine, with mean terminal half-lives of 34.9 h (R) and 49.6 h (S). The terminal half-lives of total amlodipine (mean 44.2 h) were strongly correlated with--and thus highly predictive for--the half-lives of the (S)-enantiomer. It is proposed that the observed enantioselectivity of oral amlodipine is due to differences in the systemic blood clearance of the enantiomers.

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1 The plasma kinetics and urinary excretion of glyceryl-1-nitrate (G-1-N), a metabolite of glyceryl trinitrate with antianginal potential, were investigated in 10 healthy male volunteers, after intravenous infusion and oral administration of 20 mg G-1-N. 2 The apparent volume of G-1-N distribution was 601 corresponding to 0.761 kg-1 body weight, on average. It is suggested that total body water is the principal biological correlate of the hydrophilic drug.3 Mean intravenous clearance was 283 ml min-' or 3.61 ml min-1 kg-1. The average of elimination half-lives were 2.50 ± 0.36 (s.d.) h after the intravenous and 2.54 ± 0.40 (s.d.) h after the oral dose. 4 Inter-subject variances of pharmacokinetic parameters were low compared to variances reported for glyceryl trinitrate. The coefficient of intra-subject variation of the elimination half-lives was 8.8%. 5 5.5% (i.v.) and 5.4% (p.o.) of the administered dose were excreted into urine up to 48 h after the administration. 1% (i.v.) and 1.5% (p.o.) were in the conjugated form. 6 The oral dose was rapidly and almost completely absorbed. The oral bioavailability on the basis of areas under the curve amounted to 88.6% on the average. 7 For clinical use, owing to its high oral bioavailability, long residence in the body, inactivation by metabolic conversion, and good predictability of kinetic parameters, G-1-N offers advantage over glyceryl trinitrate.

In vitro experiments were performed on isolated articular chondrocytes under the influence of piroxicam. It was demonstrated that this non-steroidal anti-inflammatory agent affected neither cell proliferation nor the incorporation of 35SO4 into matrix macromolecules. Dogs were treated with piroxicam for 8 weeks. Morphological studies were performed on the tissues of the knee joints. Macroscopic and light microscopic investigations revealed no structural differences between the tissues (synovial membrane and articular cartilage) of control and treated dogs. Even at the ultrastructural level no alterations in the cartilage were observed. The capacity of chondrocytes to incorporate 35SO4 under in vitro conditions was identical in control and experimental animals. It is concluded that piroxicam has no adverse effect on chondrocytes under in vitro conditions or on articular cartilage structure in the in vivo model.