Seven normal human volunteers each received a constant-rate infusion of chlorthalidone for 2 h, and the same (commonly 50 mg) single oral dose on separate occasions. The concentration of unchanged chlorthalidone was analyzed over a 100 to 220 h period in plasma, red blood cells, urine and faeces after both dosage forms. A three compartment model was required to describe the intravenous plasma concentrations in five of the subjects. A two compartment model sufficed to account for the decay of the oral plasma concentrations in all seven subjects. The mean plasma t1/2 after i.v. dosing was 36.5 h (+/- 10.5 SD), and the mean plasma t1/2 after oral doses was 44.1 h (+/- 9.6 SD). The mean red blood cell concentration t1/2 after i.v. doses was 46.4 h (+/- 9.9 SD), and the mean red blood cell t1/2 after the oral doses was 52.7 h (+/- 9.0 SD). The shorter i.v. half-live was not equally manifest in all subjects, being mainly apparent in three of them. In all cases the urinary excretion rate plots were parallel to the plasma concentration curves. As the faster decay after i.v. administration was not accompanied by increased renal clearance, the difference must have been due to non-renal mechanism. The mean total of 65.4 (+/- 8.6 SD) % of the intranvenous dose was excreted in urine over infinite time, whereas the mean total excretion after the oral dose was 43.8 (+/- 8.5 SD) %. Faecal excretion ranged from 1.3--8.5% of dose in the i.v. study to 17.5--31.2% of dose in the oral study. The sum of the amounts present in urine plus faeces pointed strongly to an important metabolic route of elimination of chlorthalidone. Bioavailability estimates (F) from three sets of data were--a mean F of 0.61 from plasma concentrations, 0.67 from urinary excretion measurements and 0.72 from the erythrocyte concentrations. Simulations with a non-linear model indicated lesser validity of the estimate from erythrocyte concentrations. It was concluded that the average of plasma and urine data, F = 0.64, yielded the best estimate of the oral availability of chlorthalidone 50 mg in man.

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Renal excretion, plasma concentration, and erythrocyte concentration profiles of chlorthalidone were studied in 17 healthy human subjects for 100 to 200 hr after oral administration of single doses of 50, 100, or 200 mg. Three subjects received all three doses in a crossover design. The other 14 were involved in the study at one dosage level. The 50-mg dose was taken altogether by 6 subjects, the 100-mg dose by 11, and the 200-mg dose by 6. Total urinary recovery of chlorthalidone extrapolated to infinity was 44.4% of the 50-mg dose (22.2 ± 3.4 mg), 43.1% of the 100-mg dose (43.1 ± 4.7 mg), but only 29.0% of the 200-mg dose (58.0 ± 9.7 mg; mean values ± SD). There was a large interindividual variation in the renal plasma clearance of chlorthalidone (52 to 125 ml/min after 50 mg, 43 to 107 ml/min after 100 mg, and 47 to 77 ml/min after 200 mg). This variation correlated more with differences between subjects in the area under the plasma concentration curve than with those in total urinary recovery of the drug. The subjects available for between-dose comparison showed an average decrease of 27% in renal clearance in going from the single 50-mg to the 200-mg dose, suggesting a causal relationship with the limited urinary recovery of the drug at the higher dose. These pharmacokinetic results indicate that the known antihypertensive dose-response curve of chlorthalidone in man may well be related to the extent of its urinary recovery.Diuretics playa crucial role in current treatment of mild to moderate hypertension. Several recent studies have compared the antihypertensive effects of different dosage levels of chlorthalidone (hygroton), ranging from 12.5 to 200 mg daily. 3,7,18,20 The general conclusion was ing in a reduced extra-cellular volume, and the antihypertensive effect of diuretics seems to be firmly established. 4 , 8 On the other hand, there are indications of a dependence of natriuresis on the excretion in the urine of the diuretic drug itself, which was demonstrated in the case of chlorothiazide,5 hydrochlorothiazide,6 and furosemide \5-\7 by interaction studies with probenecid. These considerations suggested a study of the involvement of pharmacokinetic factors, with emphasis on the urinary excretion parameters, in the clinical dose-response curve of chlorthalidone.that with the 25-mg dose, equal or almost equal blood pressure reductions were achieved compared with larger doses. Methods Subjects and dosage.Single oral doses of chlorthalidone were administered as commer- 806