Donald R. Kay

Pharmacokinetics of ethanol after oral administration in the fasting state

A nonlinear relationship between the total area under the blood ethanol concentration-time curve and the orally administered dose (mg/kg) of ethanol was observed in fasting subjects. A preliminary model, based on physiological considerations, was elaborated and shown, for the first time, to describe the entire time course of blood alcohol concentrations after four different doses of alcohol. The model could be refined by further experimentation.

Penicillamine kinetics in normal subjects

The kinetic characteristics of penicillamine are reported in four fasting subjects after four oral doses each. On later test days, two of the subjects received an additional single dose 30 min after a large breakfast. One subject originally included in the study had to drop out because of gastrointestinal disturbances following each of two single doses of penicillamine. The fasting plasma levels of penicillamine observed in this study displayed an unusual double peak in the plasma levels after single doses. Individual subjects had consistent plasma level patterns for each of the four single doses but there was marked intersubject variability in patterns and kinetic parameters. The half‐life of unchanged penicillamine ranged from 1.66 to 3.15 hr and the apparent plasma clearance ranged from 530 to 2300 ml/min. The administration of penicillamine following a large breakfast caused a reduction in the area under the penicillamine plasma concentration‐time curve corresponding to a decrease in the extent of absorption of unchanged penicillamine.

Dose-response studies of the suppression of whole blood histamine and basophil counts by prednisone

If some clinical problems (e.g., radiographic contrast media reactions) arise from mediator release by circulating basophils, prednisones capacity to prevent such is likely to be at least partly related to its suppressive effects on whole blood histamine and basophil levels. To establish an optimal dosage schedule, 15 healthy male volunteers entered a two-phased study to determine (1) the single dose of prednisone required to produce maximal suppression of histamine and basophil levels and (2) the effects of repeated prednisone doses. Parameters monitored were whole blood histamine, quantitative basophil counts, white blood cell (WBC) and differential counts, and plasma prednisone, prednisolone, and cortisol levels. Fifty milligrams prednisone suppressed whole blood histamine levels as much as a larger dose and also showed a marked effect on circulating basophils and other leukocytes. Three 50-mg prednisone doses given at 6-hr intervals had a greater effect on whole blood histamine and circulating leukocytes than fewer doses. Thus, the commonly used empirical prednisone dosage regimen is supported. One implication of the results of this study is that greater suppression of blood basophils and histamine levels might be obtained by administering the last prednisone dose about 6 hr before procedures in which a very rapid release of mediators from basophils is anticipated.

High-performance liquid chromatographic determination of penicillamine in whole blood, plasma, and urine

A high-performance liquid chromatographic method for the determination of penicillamine in plasma, whole blood, and urine samples is described. The method uses a commercially available electrochemical detector at a potential of +0.1 V versus the Ag/AgCl reference electrode. This method is selective and sensitive for sulfhydryl compounds. The chromatography separates penicillamine from other endogenous sulfhydryl compounds with a limit of detection for penicillamine in biological samples of ca. 10(07) M.

The in vitro loss of penicillamine in plasma, albumin solutions, and whole blood: Implications for pharmacokinetic studies of penicillamine

Abstract The recent development of a high performance liquid chromatography assay method for the analysis of penicillamine in biological samples such as plasma, whole blood, and urine has provided a specific and sensitive assay method to aid in the study of penicillamine pharmacokinetics. Several investigators have reported measuring the plasma concentration of penicillamine. Some of these investigators have indicated that the plasma must be assayed immediately. However, such restrictions can limit the feasibility of a pharmacokinetic study. The results of this paper demonstrate the instability of penicillamine in plasma, albumin solutions, and whole blood. The rate of loss of penicillamine was shown to be influenced by the concentration of albumin. As a result of the significant loss of penicillamine over a short period of time, plasma or whole blood samples must be deproteinated immediately upon collection to avoid the loss of reduced penicillamine. Methods are presented for the preparation of biological samples so that the oxidation of penicillamine is prevented and the samples can be held for several days prior to analysis.

Plasma protein binding of prednisolone in normal volunteers and arthritic patients.

SummaryThe plasma binding of prednisolone was studied in twenty normal volunteers and twenty rheumatoid arthritis patients. An in vitro assessment of the binding following the addition of prednisolone, prednisone, and hydrocortisone to the plasmas obtained from the subjects showed significant differences in the percentage of prednisolone bound. However, the differences observed were regarded as clinically insignificant. The plasma protein binding was determined by an in vitro equilibrium dialysis of the individual plasma samples at 37° C. Prednisolone levels on both sides of the dialysis membrane were determined using radioactivity and HPLC analytical methodologies. The percentages of prednisolone bound calculated from the analytical results of either the radiochemical or HPLC method were not significantly different. The change in the percentage of prednisolone bound to plasma proteins was studied as a function of the total prednisolone plasma concentration in a normal volunteer and in a systemic lupus erythematosis patient. As a result of prednisolone binding to both transcortin and albumin, the binding of prednisolone changes as a function of prednisolone concentration. The binding data were fitted using nonlinear least squares regression, and the affinity constants for the binding of prednisolone to transcortin and albumin were estimated.

The pharmacokinetics of penicillamine in a female mongrel dog

The pharmacokinetic parameters of D-penicillamine were investigated by administering four intravenous bolus doses, four oral doses, and six constant rate intravenous infusions to a female mongrel dog at dosages comparable to 250, 500, 750, and 1000 mg in man. The pharmacokinetics of D-penicillamine demonstrated nonlinearity in the dog. There was more than proportional increase in the area under the whole blood concentration curve for an increase in the bolus intravenous dose. The steady state whole blood, plasma, and packed cell levels of penicillamine were increased more than proportionately for an increase in the intravenous infusion rate. Total body clearance of penicillamine was decreased by increasing the dose or the infusion rate of penicillamine. Correspondingly, the estimated half-life of unchanged penicillamine in the whole blood was decreased for increased intravenous bolus doses. The renal clearance of penicillamine was nonlinear, decreasing with time during the bolus experiments and increasing at higher infusion rates. The nonrenal clearance was decreased at higher infusion rates, suggesting that a saturable nonrenal elimination process exists for penicillamine in the dog. The nonlinearities that were observed in the dog, if also present in man, may be responsible in part for the dose related side effects reported clinically for penicillamine.

Radiological aspects of the arthropathy of relapsing polychondritis

Relapsing polychondritis is a cause of sacro-iliac arthritis with bone erosion, but the peripheral arthritis in this condition is not usually associated with bone erosion.