Reproducibility of the distribution of carbon-11-SCH 23390, a dopamine D1 receptor tracer, in normal subjects.

UNLABELLED: The reproducibility of [11C]SCH 23390 in PET was studied in 10 normal human subjects. METHODS: The scan-to-scan variation of several measures used in PET data analysis, including the radioactivity ratio, plasma-input Logan total distribution volume (DV), plasma-input Logan DV ratio (DVR) and tissue-input Logan Bmax/Kd values, was determined. RESULTS: There were significant correlations among the radioactivity ratio, plasma-input DVR and tissue-input Bmax/Kd. With the cerebellum as the reference region, these three measures also had high reliability (86%-95%), high between-subject s.d. (7.7%-11.3%) and small within-subject s.d. (2.3%-3.6%), indicating that they are comparable and useful measures for the assessment of dopamine D1 receptor binding. CONCLUSION: The radioactivity ratio and the tissue-input Bmax/Kd may be preferred methods for the evaluation of dopamine D1 receptor binding because these two methods do not require arterial blood sampling and metabolite analysis. Our results show that cerebellum is a reliable reference region for SCH 23390. When the Logan plasma-input function method is used in data analysis for SCH 23390, DVRs rather than total DV values should be used because of the poor reliability of the DV values and their lack of correlation with other measures. Carbon-11-SCH 23390 is thus a reliable and reproducible ligand for the study of dopamine D1 receptor binding by PET.

Cyclosporin: measurement of fraction unbound in plasma.

A reproducible ultracentrifugation method has been developed for the measurement of the fraction of cyclosporin (CyA) unbound in plasma. The sample is centrifuged to remove any particulate matter, ultracentrifuged in polyallomer tubes and then frozen in liquid nitrogen. Appropriate sections are then cut from the tube for determination of the concentration of radioactivity and calculation of fraction drug unbound. Using this method, the fraction unbound has been measured in plasma from renal transplant patients receiving CyA and found to range between 0.04 to 0.122. The binding is temperature-dependent and principally hydrophobic.

Cyclosporin: erythrocyte binding and an examination of its use to estimate unbound concentration.

Cyclosporin A (CyA) undergoes saturable binding to erythrocytes. Theoretically, measurement of erythrocyte concentration can be used to estimate the unbound concentration, which in turn may be more closely related to response than total plasma concentration. This possibility for estimating unbound concentration was explored in 139 blood samples taken from renal transplant patients who received CyA therapy. In practice, the method proved to be no better than that obtained by assuming a constant fraction CyA in plasma unbound. In this study, however, both methods were too imprecise to be of practical value. If unbound CyA concentration is to be determined it must be measured directly or must be estimated by multiplying total plasma concentration by fraction of drug unbound.

Saturable binding of cyclosporin A to erythrocytes: estimation of binding parameters in renal transplant patients and implications for bioavailability assessment.

Cyclosporin (CyA) exhibits saturable binding to erythrocytes. A one-site binding model was fitted to data from renal transplant patients receiving CyA therapy. The average maximum binding capacity is 2560 micrograms CyA/liter of packed erythrocytes; the unbound CyA concentration associated with 50% saturation of the binding site is 67 micrograms/liter. Analysis indicates that whole-blood CyA measurement to monitor drug therapy should be viewed cautiously, particularly when the hematocrit varies considerably. The error in estimating absolute bioavailability at steady state from whole-blood measurements, resulting as a consequence of the saturable binding, has been explored. Although extrapolation to the therapeutic situation, which involves transient drug administration, is difficult, errors of up to 25% are anticipated. When an accurate estimate of bioavailability is required, analysis based on plasma data is proposed. For bioequivalence testing, both blood and plasma CyA data are equally acceptable.

A model to account for the variation in cyclosporin binding to plasma lipids in transplant patients.

The usefulness of therapeutic monitoring for cyclosporin in transplant patients is still open to question due to variability of the data. One source of variability, the binding within plasma, was examined in renal transplant patients undergoing cyclosporin therapy. The fraction unbound varied between 0.04 and 0.13. A model based on physiochemical principles, involving concurrent partition of the drug between water, cholesterol, and triglyceride, was used to account for the variation in binding. Simulations using this model indicate that plasma cholesterol is a major factor contributing to the variability in fraction unbound and that the effect of triglyceride is less by a factor of four.

Effects of acamprosate on ethanol-seeking and self-administration in the rat.

BACKGROUND: Acamprosate (calcium acetyl homotaurinate) has been used clinically to treat relapse in alcoholics. In rats, it has been shown to decrease ethanol, but not water, self-administration after ethanol deprivation. METHODS: To further investigate the effect of acamprosate on reinforced behaviors in rats, the present experiment used: (1) both ethanol and sucrose reinforcer solutions to better assess the distinct effects of acamprosate on ethanol-directed behaviors, and (2) an operant model that procedurally separates the "cost" to begin drinking from consuming the reinforcer solutions to dissociate the effects of acamprosate on appetitive versus consummatory processes. In daily sessions (5 days/week), rats (n = 6/group) were trained to make 30 lever-press responses to gain access for 20 min to a sipper tube containing either ethanol (10%) or sucrose (3%). After stable responding, acamprosate treatment was given. Three doses were tested (50, 100, and 200 mg/kg/injection, intraperitoneally), one dose per week. Each week, a total of four injections were given (21 and 2 hr before the operant sessions over 2 consecutive days). RESULTS: At these doses, acamprosate had no effect on the measures of appetitive responding for either solution. However, all doses reliably decreased ethanol consumption on the 2nd day of treatment (from an average of 0.83 to 0.63 g/kg). Analysis of the pattern of ethanol consumption showed that the effects of acamprosate occurred after the onset of a normal pattern of intake, as measured by lick rate and size of the initial bout of drinking, which suggested that acamprosate is most effective when combined with the pharmacological effects of ethanol. Sucrose intake was unaffected by all acamprosate treatments, which indicated that the treatment effects were specific to ethanol and not due to a general decrease in consummatory behavior. CONCLUSIONS: Overall, these results suggest that acamprosate is effective at reducing total ethanol intake, but may not reliably alter subjects propensity to begin a drinking bout as measured by this model. However, whether this applies to the clinical use of acamprosate, where other types of reinforcement may also precipitate relapse drinking, is not certain.

Cyclosporin: pharmacokinetics and detailed studies of plasma and erythrocyte binding during intravenous and oral administration.

On the basis that unbound concentration better correlates with response than total plasma or blood concentration, the inter- and intra-subject variability in the distribution of cyclosporin within blood and to plasma components was studied in renal transplant patients. Pharmacokinetic aspects were also studied. Blood samples were analysed from patients who received the drug both by a 72-h i.v. infusion and orally (7 mg.kg-1 twice daily). Steady-state was reached within 18 h of starting the i.v. infusion; the plasma data were best fitted by a biexponential equation with half-times of 0.13-1.02 h and 4.3-13.9 h, associated with the two phases. The mean plasma clearance was 700 ml/min. Concentrations during the infusions measured by RIA and HPLC were comparable. Oral profiles showed rapid and extensive absorption. The peak plasma concentrations were 1460-1880 micrograms.l-1 and occurred 2-4 h after dosing, with bioavailability estimates of 41-113%. Concentrations measured by RIA were higher than by HPLC. Blood-to-plasma concentration ratio measurements of cyclosporin at 37 degrees C decreased with increasing plasma concentration and increased with haematocrit. Fraction unbound, measured by ultra-centrifugation, was in the range 0.042-0.122 with an average of 0.068, and varied little in some patients but showed systematic changes with time in others. Cyclosporin binding was found to be related not only to the triglyceride but, more particularly, to the cholesterol-related lipoproteins in plasma. Monitoring cholesterol may be helpful in identifying patients with extremes in binding or with widely varying binding.

Pharmacokinetics of cyclosporin: influence of rate of constant intravenous infusion in renal transplant patients.

1 The pharmacokinetics of cyclosporin were studied in 12 renal transplant patients. Five patients received a constant rate (7 mg kg-1 day-1) intravenous infusion over 72 h and the remainder received rates of 7, 4 and 10 mg kg-1 day-1, consecutively each for at least 24 h. 2 Plasma, separated at 37 degrees C, was analysed by h.p.l.c. 3 The data were best described by a biexponential model. 4 Following the 72 h infusion, a plateau was reached by 24 h and clearance was 0.60 l h-1 kg-1. 5 Clearance associated with the 10 mg kg-1 day-1 infusion rate (0.43 l h-1 kg-1) was estimated to be lower than that following the 4 and 7 mg kg-1 day-1 rates (0.52 and 0.54 l h-1 kg-1 respectively) but the difference is unlikely to be of clinical significance.

Pharmacokinetics of ticarcillin in man.

The excretion of radioactivity has been investigated in 3 healthy volunteers following rapid intravenous administration of 5 g of [35S]-ticarcillin. The radioactive dose was rapidly and completely excreted, since within 4 days 98.5% was recovered, 95% in the urine and 3.5% in faeces. All the urine radioactivity was accounted for as ticarcillin and its penicilloic acid. Plasma and urine samples collected from the volunteers at frequent intervals during the first 6 h of the experiment were assayed for penicillin by an automated chemical method and also for radioactivity. The results obtained by the chemical autoanalyser method were in excellent agreement with the plasma levels of radioactivity. From the data it was possible to calculate the renal clearance of the penicillin, a mean value of 104 ml/min was observed in the 3 volunteers. A further three volunteers were dosed intravenously with a 5 g bolus of non-radiolabelled ticarcillin in a cross-over study with and without predosing with probenecid. Serum samples were analysed by the chemical method for penicillin and the data subjected to pharmacokinetic analysis using a two compartment open model. The results indicate a shift of the distribution equilibrium of ticarcillin from the serum into the peripheral compartment after predosing with probenecid. Furthermore, the mean half-life of ticarcillin in the serum of the three volunteers was significantly increased from 1.3 h to 2.1 h by predosing with probenecid.