F. Bochner

Plasma protein binding of carbamazepine.

The binding of carbamazepine to the pro teins of human plasma has been studied using ultrafiltration techniques. In vitro studies at 37° C showed the relation between concentration of unbound drug and total drug to be linear thraugh the range of total concentration of 5 to 50 µg/ml. The per cent unbound drug increased slightly as concentration increased. There was tittle difference between the extent 0/ binding at 4° C and 20° C, but more carbamazepine was unbound at 37° C. Under in vitro conditions, 6 other anticonvulsants, and aspirin, were tested individually, each at high therapeutic or toxic concentration, and shown not to displace carbamazepine from plasma proteins to a significant degree. The extent of binding of carbamazepine in vivo was determined in a total of 54 plasma sampies collected from treated patients; 26.9 ± SD 9.4% of the drug was unbound. In blood sampies from 23 of these patients, the red cell concentration of carbamazepine averaged 38.3 ± SD 17.9% of the plasma concentration. The effects of hepatic and renal diseases on the carbamazepine binding capacity of plasma proteins were assessed by comparing the binding capacity of plasma from diseased persons with that from normal subjects. There was no significant difference in binding capacity between plasma from patients with renal disease and that from normal subjects. However, the plasma from patients with hepatic disease bound a stightly lower percentage of carbamazepine than did normal plasma (p < 0.05). This alteration did not correlate with changes in any of 15 biochemical parameters measured in these patients. The clinical significance of these results is discussed.

Dose-dependent prednisolone kinetics.

Kinetic data for prednisolone and prednisone have been determined following oral administration of prednisolone over a dosage range of 5 to 200 mg in 43 subjects. Intravenous studies have been performed at 20 mg and 100 mg in 3 subjects. At all dosage levels the elimination t½β for prednisolone remained constant (t½β 3.5 ± 0.2 hr [20 mg], t½β 3.7 ± 0.1 hr [100 mg] mean ± SEM). For prednisolone, there was a linear relationship between dose and AUC0→∞ and Cmax up to a dose of 20 mg, but above this level AUC00→∞ and Cmax demonstrated a less rapid increase as the dose increased. The prednisone AUC0→∞. remained a constant proportion, 26 ± 2%, of the prednisolone AUC0→∞ at all dosage levels. Bioavailability of prednisolone was 98.5 ± 4%. There was a constant amount of prednisolone bound to cortisol‐binding globulin (CBG) (145 ± 16 ng/ml) and as a proportion of the remaining serum prednisolone, the free remained at 14 ±2% and non‐CBG protein‐bound prednisolone at 86 ± 2% over the whole dosage range. The intravenous studies demonstrated a significant difference in the volume of distribution of prednisolone as the dose changed from 20 mg (Vd 58 ±4 L) to 100 mg (Vd 90 ± 6 L). Since it has been demonstrated that bioavailability, serum protein binding, prednisone‐prednisolone interconversion, and t½β remained constant over this dosage range, the altered Vd may account for the nonlinear relationship between AUC and dose.

Single-dose pharmacokinetics of metoclopramide

SummaryThe time courses of plasma metoclopramide concentrations were followed in six subjects after oral and intravenous single dose administration. Plasma concentration-time data following i.v. administration in each subject were found to fit a two compartment model with a mean terminal half-life of 4.55 h±0.80 h and a mean distribution half-time of 0.35 h±0.09 h. Volumes of distribution were high (3.43±1.181 · kg−1), and clearances (0.53±0.191 · kg−1h−1) approached liver plasma flow. This suggests that metoclopramide occurs at higher concentrations in tissues than in plasma, and that its clearance is probably limited by liver blood flow rather than liver metabolic capacity. The post-absorption decline in metoclopramide plasma levels after oral administration was also biexponential in each subject. The terminal half-life was 5.17 h±0.98 h. Mean volume of distribution and mean clearance were similar to intravenous values (after adjustment for bioavailability). Oral absorption was rapid with peak plasma concentrations being reached at a mean time of 0.93 h. A mean bioavailability of 0.77 was calculated for the six subjects, and it was postulated that this incomplete availability is due to a first-pass effect. The inter-individual variation in the degree of ‘first-pass’ was considerable (0.47–1.14).

Factors involved in an outbreak of phenytoin intoxication

An outbreak of phenytoin intoxication occurred in Australia in 1968 and 1969 following a change in the excipient in one brand of phenytoin sodium capsules. The major excipient component, calcium sulphate, was replaced by lactose and the minor components of the excipient were increased in quantity. In 12 of 13 patients in a cross-over study phenytoin with calcium sulphate excipient produced lower blood phenytoin levels than phenytoin with lactose excipient. In individual patients, study of the effects of various combinations of the excipient components under consideration showed that only calcium sulphate was capable of producing changes in blood phenytoin concentrations. A phenytoin balance study showed that plasma phenytoin levels fell when phenytoin (lactose excipient) was replaced by the same daily dose (400 mg) of phenytoin (calcium sulphate excipient): at the same time faecal phenytoin excretion increased by a mean of 100 mg daily. Approximately 25% of the drug in the capsules with calcium sulphate excipient was in a form with solubility properties different from those of phenytoin itself, but identical with those of the extra faecal phenytoin excreted when phenytoin (calcium sulphate) was taken. Therefore the presence of calcium sulphate in the phenytoin excipient appeared to convert part of the drug to an unabsorbable form. Thus, administration of phenytoin capsules without calcium sulphate as the major excipient produced higher blood phenytoin concentrations and instances of drug intoxication in epileptics previously stabilised on phenytoin (calcium sulphate excipient).

Electron-capture gas chromatographic assay for metoclopramide in plasma

An original electron-capture gas chromatographic assay has been developed for the quantiation of metoclopramide in human plasma. The method involves derivatization with heptafluorobutyryl imidazole after alkaline extraction, acid backwash, and a further alkaline extraction. Plasma levels of metoclopramide as low as 5 micrograms/l can be measured using 1 ml of plasma, and no interference from related substances or commonly prescribed drugs has been found. The percentage recovery of drug from plasma ranges from 88% to virtually 100%, and the between-run variation in the assay is 4.3%. The assay has been used for the study of metoclopramide pharmacokinetics in man following intravenous single-dose administration. The resultant plasma concentration vs. time curve was biexponential, with a terminal half-life of 5.0 h, and a distribution half-time of 0.3 h.

The elimination of phenytoin in man

1. Plasma phenytoin (diphenylhydantoin) levels after different drug doses were correlated with urinary 5‐(p‐hydroxyphenyl)‐5‐phenylhydantoin (p‐HPPH) excretions in four subjects.

The renal handling of diphenylhydantoin and 5‐(p‐hydroxyphenyl)‐5‐phenylhydantoin

The renal clearances of diphenylhydantoin (DPH) and its maior metabolite, 5‐(p‐hydroxyphenyl)‐5‐phenylhydantoin (HPPH) have been measured in groups of 16 and 14 ambulant epileptic patients, respectively. All patients had normal renal function (creatinine clearances, 83 to 148 ml per minute), and were taking oral diphenylhydantoin sodium in doses of 300 to 500 mg per day. DPH clearance (3 to 23 ml per minute, depending on urine flow rate) was considerably less than that expected for inulin, and it seems probable that DPH undergoes net resorption in its passage through the kidney. HPPH clearance (76 to 420 ml per minute depending on urine flow rate) exceeded expected inulin clearance if urine flow rates were sufficiently high, allowing the Stlggestion that net secretion of HPPH occurs during its passage through the nephron. Although the clearances of both compounds increase with urine flow rate, it is concluded that neither oliguria nor polyuria would be likely to greatly influence plasma DPH concentration in the short term, making dosage adiustment in these two circumstances unnecessary, at least as a matter of urgency.

Prednisolone pharmacokinetics in asthmatic patients

Prednisolone serum levels have been measured by radio-immunoassay in 12 steroid-dependent asthmatic patients. Differences in prednisolone pharmacokinetics did not account for the variation in dose of prednisolone required to control asthma.

Possible acute liver toxicity from the hypolipidemic agent 1-methyl-4-piperidyl-bis(p-chlorophenoxy)-acetate.

Abstract In the course of a pilot study to evaluate the hypolipidemic agent, 1-methyl-4-piperidyl-bis( p -chlorophenoxy)-acetate (SaH 42–348), hepatotoxicity was encountered in 1 patient. Biochemical and histologic evidence was obtained which strongly suggested that the hepatic alteration was associated with the treatment.

Use of an Ergot Preparation (Hydergine) in the Convalescent Phase of Stroke

Hydergine (1 mg three times daily) or placebo was administered orally to geriatric patients who were convalescing from stroke. Twenty‐one patients were studied in a 12‐week double‐blind trial, and 15 in a 12‐week double‐blind cross‐over study. Regular assessments were made of symptomatology, physical, mental and psychological status and recovery from paralysis. Statistical analyses of the results of both studies showed that there was no significant difference between the effects of Hydergine and of placebo. The possible relationship between cerebral function, cerebral arteriosclerosis and cerebral blood flow is discussed.