Search

1. We have given an oral load of lithium carbonate to healthy volunteers in order to investigate the transport of lithium across the erythrocyte membrane in vivo and the effects of known inhibitors of that transport. 2. Using this technique we have shown that pretreatment with either digoxin, an inhibitor of the sodium/potassium pump, or dipyridamole, an inhibitor of the anion transporter, does not alter the plasma or erythrocyte lithium concentration profiles, nor any of the pharmacokinetic variables derived from these data, and we conclude that these two transport pathways do not contribute significantly to the in vivo handling of lithium by erythrocytes. 3. We have also shown that erythrocyte lithium concentrations measured directly differ significantly from the predicted concentrations calculated using the two-compartment pharmacokinetic model which has been used in some earlier comparisons of in vitro and in vivo lithium handling. 4. We suggest that the in vivo administration of lithium carbonate may permit a specific measure of the in vivo activity of the sodium/sodium countertransport pathway. [ABSTRACT FROM AUTHOR]

Amodiaquine hydrochloride (3 mg base kg-1) was given by constant rate intravenous injection over 10 min to seven healthy adult male volunteers, and by constant rate infusion (10 mg base kg-1) over 4 h to 10 adult patients admitted to hospital with falciparum malaria. After intravenous injection in volunteers there was considerable variation in plasma concentration profiles between subjects; peak plasma concentrations ranged between 65 and 1921 ng ml-1. A biexponential equation was fitted to the plasma concentration time data and the following estimated pharmacokinetic parameters (geometric mean; range) were derived; lambda 1 = 24.4 (7.6-95.0) h-1, lambda 2 = 0.33 (0.12- 0.79) h-1, V1:1.1 (0.3-3.6) 1 kg-1, Vss: 17.4 (2.3-95.9) 1 kg-1 and systemic clearance 13.0 (4.7-56.6) 1 kg-1 h-1. After intravenous infusion there was also considerable variability between patients with post-infusion plasma concentrations ranging between 82 and 836 ng ml-1. The plasma concentration-time profiles were biphasic with the following estimated pharmacokinetic parameters (geometric mean; range) alpha = 1.87 (0.60-8.52) h-1, beta = 0.069 (0.021-0.265) h-1, V1: 4.6 (0.5- 29.3) 1 kg-1, Vss: 38.3 (3.7-127.9) 1 kg-1 and systemic clearance CL (1.6-17.3) 1 kg-1 h-1. There was no measurable long terminal elimination phase, and the principal metabolite desethyl amodiaquine was not detected in the plasma samples. There was no serious toxicity in either group. During intravenous injection there was a significant fall in systolic blood pressure in four subjects (mean fall 16 mm Hg) but there was no significant change in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

Chloroquine diphosphate (3 mg base kg-1) was given by constant rate intravenous injection over 10 min to 12 healthy adult male volunteers. Plasma concentrations of chloroquine and the principal metabolite desethylchloroquine, electrocardiograph intervals, and arterial blood pressure were measured at frequent intervals to determine the relationship between cardiovascular effects and plasma concentrations. Peak plasma concentrations ranged between 784 and 6649 (mean 2913) ng ml-1. The decline in plasma concentrations was multiexponential with an initial rapid distribution phase; mean (+/- s.d.) first order rate constant 0.65 +/- 0.14 min-1, and an estimated apparent volume of the central compartment of 0.18 +/- 0.15 l kg-1. There was no serious toxicity, but subjective side effects were reported in all patients and there was a significant fall in systolic blood pressure (110 +/- 9.5 to 101 +/- 12.5 mm Hg; P = 0.03) and rise in heart rate which paralleled the change in plasma chloroquine concentrations. Coincident with changes in blood pressure, there was a significant prolongation of the electrocardiograph QRS interval; 81 +/- 15 to 92 +/- 13 ms (P less than 0.01) but no change in the QTc interval. These findings suggest that the cardiovascular toxicity of parenteral chloroquine is related to transiently high plasma concentrations occurring early in the distribution phase. This results from incomplete distribution from a central compartment that is approximately one thousand times smaller than the eventual total apparent volume of distribution at steady state. Rate of administration is therefore a major determinant of toxicity. [ABSTRACT FROM AUTHOR]

Intravenous quinine dihydrochloride (5 mg kg-1 over 5 min) was given to seven healthy male volunteers. There were minor subjective symptoms in all subjects but no significant changes in pulse or blood pressure. There was significant prolongation of the electrocardiographic QRS and rate corrected QT intervals which was greatest between 1 and 4 min after completion of the quinine infusion. Values then returned towards baseline. Plasma concentrations of quinine were measured spectrophotofluorimetrically after benzene extraction. Peak plasma concentrations (mean +/- 1 s.d.) after the infusion were 5.1 +/- 1.3 mg 1(-1). Pharmacokinetic analysis fitted a two compartment open model in each case; distribution half-time (t 1/2, lambda 1) was 1.89 +/- 0.54 min (mean +/- 1 s.d.), elimination half-time (t 1/2, z) 11.1 +/- 2.1 h, apparent volume of the central compartment (V1) 0.57 +/- 0.32 1 kg-1, total apparent volume of distribution 1.80 +/- 0.37 1 kg-1 and total clearance 1.92 +/- 0.45 ml min-1 kg-1. [ABSTRACT FROM AUTHOR]