John H. Tyrer

Plasma protein binding of diphenylhydantoin. Effects of sex hormones renal and hepatic disease.

The in vitro binding of diphenylhydantoin (DPH) to the protein in plasma from 97 volunteers has been studied using ultrafiltration at 37° C. The capacity of plasma protein to bind DPH did not differ significantly between pregnant women (11.6 ± 1.7% of total drug unbound), women taking oral contraceptives (9.9 ± 1.7% unbound), healthy males (10.6 ± 1.3% unbound), and healthy females (11.0 ± 3.2% unbound). However, in plasma trom patients with renal disease (15.8 ± 3.9% unbound), hepatic disease (15.9 ± 6.0%) or hepatorenal disease (15.6 ± 5.4%), the protein binding of DPH was significantly decreased. These changes in protein binding were found to correlate better with changes in albumin and bilirubin levels in plasma than with any of 13 other biochemical parameters examined.

Plasma Drug Level Monitoring in Pregnancy

During pregnancy a number of continuously changing circumstances exist which might be expected to modify the relation between plasma drug levels and drug dosage. Alimentary tract motility may be decreased, the distribution of many drugs may be altered, glomerular filtration rale is greater and biotransformation capacity may be changed as pregnancy advances. However, relatively little has been published on the monitoring of plasma drug levels during pregnancy.It has been established that, in the presence of constant drug doses, plasma levels of phenytoin, phenobarbitone and certain other anticonvulsants tend to fall during pregnancy and rise again during the puerperium. Plasma lithium and possibly digoxin levels also fall relative to drug dose as pregnancy progresses, and rise again in the puerperiuin.While the changes in lithium and digoxin levels are probably chiefly due to increased rate of glomerular filtration during pregnancy, the altered anticonvulsant requirement is more likely to depend mainly on an increased rate of biotransformation. Anticonvulsant plasma levels should be monitored regularly from the outset of pregnancy and more frequently after birth.

Factors Influencing Simultaneous Concentrations of Carbamazepine and its Epoxide in Plasma

Summary Simultaneous steady-state plasma concentrations of carbamazepine and carbamazepine-10, 11-epoxide were measured by high performance liquid chromatography in 295 patients. Plasma carbamazepine epoxide correlated more closely with carbamazepine dose than did plasma levels of the drug itself. Plasma carbamazepine epoxide levels tended to be higher, relative to drug dose, in children than in adults, whereas age did not seem to influence the relationship between plasma carbamazepine level and drug dose. Simultaneous phenytoin intake lowered the plasma carbamazepine levels relative to drug dose but left plasma carbamazepine epoxide levels largely unaltered. However, simultaneous valproate intake was associated with raised plasma carbamazepine epoxide levels relative to carbamazepine dose, whereas plasma carbamazepine levels were unaltered. The amount of conversion of carbamazepine to its epoxide thus appears to vary in different circumstances in humans.

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.

Aspirin pharmacokinetics in migraine. The effect of metoclopramide

SummaryThe pharmacokinetics of aspirin (ASA) in acute migraine attacks, and the influence of metoclopramide on ASA disposition, were studied in 32 attacks in 30 patients. An intergroup comparison was made between normal volunteers, and the migraineurs, who were assigned at random to one of three treatment groups: a) oral ASA only (900 mg); b) 10 mg oral metoclopramide + oral ASA 900 mg; c) 10 mg i. m. metoclopramide + oral ASA 900 mg. Plasma ASA and SA levels were measured serially over 2 h, and the resultant data evaluated pharmacokinetically. Metoclopramide plasma levels were also determined over 2 h, and the results compared with a second group of normal volunteers. The rates of oral ASA absorption and elimination were unaffected by migraine. Mean absorption rate constants of 14.15±9.48 h−1 (normals), 7.91±3.42 h−1 (ASA only), 6.74±3.26 h−1 (ASA + oral metoclopramide) and 8.12±2.82 h−1 (ASA + i. m. metoclopramide) were calculated. Mean elimination rate constants ranged from 2.56 h−1 to 3.37 h−1, and did not differ significantly between controls and migrainous patients. Values for absorption lag time, however, were higher in migraine patients treated with ASA alone than in any other group. The amount of ASA absorbed unhydrolysed was also lower in this group. SA levels appeared unaffected either by the migraine attack, or by metoclopramide administration, over the period of study. Metoclopramide plasma levels were significantly lower during migraine attacks, and the amount of drug absorbed up to 2 h from dosing was also reduced, as compared with non-migrainous subjects. It was concluded that acute migraine caused a delay in orally administered ASA reaching its absorption sites, probably as a result of gastric stasis, and may have decreased the amount of ASA absorbed. The prior administration of metoclopramide, either orally or intramuscularly, reduced the absorption lag time, and thus promoted the early absorption of ASA, probably by restoring alimentary tract motility.

Aspects of tetrazolium salt reduction relevant to quantitative histochemistry

SummaryUncertainty about the nature of the reduction products of ditetrazolium salts may have limited their use in quantitative histochemistry. Our studies have shown that under appropriate conditions pure Nitro-BT reduces through a red intermediate substance to a stable blue diformazan. Nitrobenzene was found to be a satisfactory solvent for this diformazan. The monotetrazolium INT may also be reduced to a formazan through an intermediate phase. The amounts of definitive formazan produced from both monotetrazolium and ditetrazolium salts may be influenced by the solubility of their intermediate reduction compounds in the systems in which reduction is occurring. The yield of definitive diformazan from Nitro-BT after chemical reduction, and after enzymatic reduction in liver homogenate and sections of a “mock” tissue, was not in linear proportion to the strength of reducing conditions; however, the yields of formazan from the monotetrazoliums INT and MTT were linear. This finding suggests that in quantitative histochemistry it is essential to calibrate reactions involving ditetrazolium reduction.

Anticonvulsant therapy : pharmacological basis and practice

Part 1 Principles: the decision to treat epilepsy principles of clinical pharmacology measurement of anticonvulsant concentrations in biological fluids the study of anticonvulsant drug action principles of therapy with anticonvulsants. Part 2 Pharmacology of individual anticonvulsants: hydantoin anticonvulsants carbamazepine barbiturate and chemically related anticonvulsants succinimides oxazolidinediones benzodiazepine anticonvulsants valproic acid sulthiame chlormethiazole. Part 3 The use of anticonvulsants in practice: the classification of epileptic seizures generalized epilepsy - absence seizures generalised epilepsy myoclonic seizures remaining varieties of generalized epilepsy and all partial epilepsy febrile convulsions in infancy neonatal seizures status epilepticus the future.

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).

The pharmacokinetics of carbamazepine.

SummaryThe time-courses of plasma carbamazepine concentrations were followed in six apparently healthy adult subjects who, at different times, took single oral drug doses of 200, 400, 500, 600, 700, 800 and 900 mg. There were some suggestions of impaired bioavailability of the drug when given in tablet form. The following values were obtained for various pharmacokinetic parameters:kabs =0.176±0.209 h−1;k=0.0203±0.0055 h−1; T1/2=37.5±13.1 h; VD=0.825±0.1041 · kg−1; Clearance=0.0163±0.0061 l · kg−1. The elimination rate constant showed a statistically significant increase with increasing drug dose. This may help explain the clinical observation that the rate of rise of steady state plasma carbamazepine concentrations tends to decrease with dose increase in patients taking carbamazepine alone.

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.