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Steady-state plasma carbamazepine levels were correlated with carbamazepine dose, expressed on a body weight basis, in 217 patients (some of whom were taking other anticonvulsants). Although there was a linear relation between plasma carbamazepine level and drug dose in the whole population studied, no such relation was found for patients taking carbamazepine alone. The factors responsible for this difference could not be identified in full, but interactions between carbamazepine and phenytoin were partly responsible.

The binding of carbamazepine to the proteins of human plasma has been studied using ultrafiltration techniques. In vitro studies at 37 degrees C showed the relation between concentration of unbound drug and total drug to be linear through the range of total concentration of 5 to 50 mug/ml. The per cent unbound drug increased slightly as concentration increased. There was little difference between the extent of binding at 4 degrees C and 20 degrees C, but more carbamazepine was unbound at 37 degrees 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 samples collected from treated patients; 26.9 plus or minus SD 9.4 percent of the drug was unbound. In blood samples from 23 of these patients, the red cell concentration of carbamazepine averaged 38.3 plus or minus SD 17.9 percent 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 disease 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 slightly lower percentage of carbamazepine than did normal plasma (p smaller than 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.

As part of a comparative bioavailability investigation, the steady-state pharmacokinetics of the anticonvulsant valproate (given as the sodium salt and the free acid) were studied in 8 epileptic patients who had received long term therapy with the drug. Mean elimination half-life was 8.21 +/- 3.13 hours, mean apparent volume of distribution 0.1868 +/- 0.0641 L/kg and mean plasma clearance 0.0177 +/- 0.0099 L/kg/hour. The magnitudes of these parameters are similar to those reported for single dose studies in patients at the start of valproate therapy. Thus, long term therapy with valproate does not appear to be associated with significant alterations in the human body's disposition of the drug, unlike the situation with certain other anticonvulsants, e.g. carbamazepine.

The pharmacokinetics and oral biovailability of dexamethasone were studied in 6 patients with neurological disease being treated with high dosages of the drug. A specific high performance liquid chromatographic assay was used to measure dexamethasone concentrations. Unlike the previously published mean figure of 0.78 for the oral bioavailability of the drug given in single doses to healthy volunteers, the mean bioavailability of dexamethasone in the patients studied was 0.53 +/- SD 0.40. It appeared more likely that this incomplete bioavailability was due to presystemic elimination than to poor absorption. The intravenous clearance of the drug was relatively high (0.4902 +/- SD 2291 1 kg-1, approximately 65% of expected hepatic plasma flow), the oral clearance higher (2.5804 +/- SD 3.2181 1 kg-1 h-1) while the absorption rate constant (4.8729 +/- 8.4998 h-1), suggested rapid absorption after oral administration. Prior phenytoin and possibly prior dexamethasone therapy is likely to have contributed to the higher clearance values of the drug in these patients than the values reported in healthy volunteers after single dose studies.

The pharmacokinetics of midazolam, an imidazo-benzodiazepine derivative, have been studied in 13 subjects over the age of 60 years who received the drug intravenously (0.07 mg kg-1) as an induction agent for endoscopy. Two to three days later, 6 of these subjects received 5 mg of midazolam intramuscularly, and another 6 of the subjects received 10 mg of the drug orally. The plasma concentration-time curves were again studied pharmacokinetically. After intravenous dosing, the mean (+/- SD) elimination half-life (2.14 +/- 1.24 h) showed a statistically significant trend to increase with age in the subjects older than 60 years. While the mean (+/- SD) clearance value (0.30 +/- 0.19 l kg-1h-1) tended to fall with age in the elderly subjects, this trend was not statistically significant. Apparent volume of distribution did not appear to be related to advancing age beyond 60 years, and this parameter (mean +/- SD) did not differ to a statistically significant extent between the aged subjects (0.77 +/- 0.47 l kg-1) and the young subjects studied previously (1.09 +/- 0.58 l kg-1). Atropine premedication did not appear to alter the dispositional parameters of the intravenously administered drug. Intramuscularly administered midazolam was absorbed rapidly. Bioavailability appeared incomplete (F = 0.59 +/- 0.15, mean +/- SD), possibly due to saturable elimination of the drug at the higher plasma levels which were obtained after intravenous midazolam. Oral bioavailability, relative to intravenous, was 0.34 +/- 0.17, (mean +/- SD), with an appreciable but variable lag time (0.74 +/- 0.40 h, mean +/- SD).(ABSTRACT TRUNCATED AT 250 WORDS)

The rate of disappearance of ergotamine from the mouth after buccal administration has been studied in seven subjects. Allowance has been made for non-absorptive losses of the drug due to experimental technique. The absorption of ergotamine across the buccal mucosa appears to be a passive process, pH-dependent but independent of ergotamine concentration or the simultaneous presence of caffeine. Because of the low solubility of ergotamine at the pH of saliva, it is unlikely that therapeutically useful amounts of the drug would have absorbed across the buccal mucosa even after the drug had been in the mouth for five minutes.

1. The bioavailabilities of carbamazepine in 100 mg and 200 mg tablets have been compared in a cross-over study of six subjects after two 600 mg doses of the drug, the different preparations being taken at 3 week intervals. 2. Areas under the plasma level curves, absorption rate constants and times to achieve peak plasma levels showed little difference between the two preparations. These findings suggest similar rates and extents of bioavailability of carbamazepine in the two preparations. 3. Calculated mean absorption and elimination parameters for carbamazepine were as follows: kabs = 0.1081 h-1, (s.d. = 0.0289); Tmax = 23.39 h, (s.d. = 8.66); k = 0.0191 h-1, (s.d. = 0.0033); VD = 0.989 1/kg, (s.d. = 0.159); and clearance = 0.0185 1/kg h, (s.d. = 0.0015).

Plasma anticonvulsant levels were followed during pregnancy in 11 epileptic women taking phenytoin and/or phenobarbital or a drug metabolized in the body to phenobarbital. As judged from the relationship between plasma level and drug dose, phenytoin requirement increased in all 10 women taking this drug during pregnancy. The requirement fell again in the puerperium. Plasma phenobarbital levels decreased during pregnancy in all five women taking a constant daily dose of phenobarbital or a congener. These findings should be borne in mind if epileptics are to be protected against seizures during pregnancy and against anticonvulsant overdosage during the puerperium.

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 rate 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 progress, and rise again in the puerperium. 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.

Two patients with severe liver damage induced by sodium valproate are described. Both were adults. One had taken valproate for longer than one year before complications developed. The other, in whom the disorder was fatal, had a predominantly 'hepatic' pattern of liver damage with centrilobular necrosis and he also developed pancreatitis. The first patient, who recovered following cessation of valproate intake, manifested a predominantly cholestatic illness with portal tract inflammation. In addition he had a degree of reversible renal failure. Neither subject had microvesicular steatosis on liver biopsy. This report indicates that valproate hepatotoxicity is not always confined to children, that it may develop much later in the course of valproate therapy than has been previously recognized, that it is not necessarily fatal if valproate intake is ceased early enough, and that it may be associated with reversible renal insufficiency.

Cytophotometric measurements of the activities of 5 enzymes (succinate, malate, and NAD+-linked isocitrate dehydrogenases from the tricarboxylic cycle, lactate dehydrogenase from the Embden-Meyerhof pathway, and NADH dehydrogenase) were correlated with cell volume for neurones in the anterior horn of rabbit lumbar and cervical spinal cord. The data for succinate and isocitrate dehydrogenases indicated that these enzymes were at higher concentrations in the smaller neurones, which consist largely of interneurones. No preferential localization to particular sizes of cell could be assigned to the other enzymes studied. The relationship between enzyme distribution patterns and their possible role in contributing toward susceptibility to ischaemia of particular sizes of neurones is discussed.

A high performance liquid chromatographic assay has been used to measure the time courses of plasma dexamethasone concentrations in patients with various neurological disorders being treated with this steroid. The pharmacokinetics of the drug in these circumstances differed from the kinetics in healthy volunteers. In particular whole body clearances were higher, causing a substantially impaired mean oral bioavailability of the drug with considerable interindividual variation in bioavailability. The clearance of dexamethasone was increased by concurrent phenytoin therapy, and dexamethasone and phenytoin are often given together in neurosurgical practice. The previously unrecognized bioavailability limitation of oral dexamethasone may explain individual instances of apparent steroid-resistant neurological disease, and suggests the desirability of monitoring plasma dexamethasone levels when using the steroid therapeutically. Some preliminary evidence has been obtained suggesting that it may be possible to avoid adrenal suppression from long-term high-dosage dexamethasone therapy, if plasma dexamethasone levels can be allowed to fall to zero between consecutive dexamethasone doses.

30 epileptic patients taking one or more of the anticonvulsants phenytoin, carbamazepine, phenobarbitone, methylphenobarbitone and ethosuximide have been studied during the courses of 34 pregnancies. In all cases the drug dosage requirement to maintain therapeutic range plasma anticonvulsant levels increased during pregnancy and fell again during the puerperium. Calculated plasma drug clearances showed a marked increase during pregnancy, reaching a peak in the third trimester, and declined again in the 3 months following pregnancy to pre-pregnancy values. For the more extensively used drugs the mean ratios of the plasma clearances in the third trimester to those in the pre- or post-pregnancy state were phenytoin 2.5:1 (p less than .001), carbamazepine 1.9:1 (p less than .005), phenobarbitone 1.6:1 (p less than .001). The limitations of the plasma clearance approach for phenytoin, a drug which is eliminated largely by Michaelis-Menten kinetic mechanisms, are discussed.

The relation between plasma phenobarbitone level and phenobarbitone dose was studied in 121 patients. The relation changed with age, the dosage requirement (on a day weight basis) tending to fall as patients grew older. Males under 5 years had a higher dosage requirement than females of the same age, but otherwise sex did not affect the relationship, nor did the concurrent intake of the anticonvulsants phenytoin, carbamazepine or sulthiame. In the individual, plasma phenobarbitone levels tended to increase out of proportion of dosage increases. These findings can provide a basis for prescribing appropriate phenobarbitone doses in epileptics.

A kinship is described in which there was slowly progressive wasting and weakness of the muscles of the upper and occasionally of the lower limbs. Some members had hyperreflexia. There were no sensory abnormalities. Electrophysiological study suggested the presence of motor peripheral polyneuropathy. The condition appeared to be inherited as an autosomal dominant. The disorder does not appear typical of any of the known hereditary polyneuropathies and it is possible that it may represent a unique hereditary, dominantly motor, polyneuropathy. The significance of the hyperreflexia is uncertain, but raises the possibility of minor central involvement as well as peripheral neuropathy.

The relation between steady-state plasma ethosuximide level and drug dose was studied in 46 patients. In this population, plasma drug levels were proportional to drug dose, expressed on a body weight basis. Age did not alter this relationship, but plasma levels increased more rapidly, relative to dose, in females than in males. Intake of methylphenobarbitone, but not intake of certain other anticonvulsants (phenytoin, phenobarbitone, primidone and carbamazepine) altered the relationship between plasma ethosuximide level and ethosuximide dose. In individual patients, successive dose increments of equal size produced progressively greater increases in steady-state plasma ethosuximide levels. This phenomenon has obvious therapeutic implications.

The 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 1 . 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.

Simultaneous steady-state plasma levels of primidone and phenobarbitone were studied in 43 patients receiving primidone therapy. Primidone and phenobarbitone levels in the individual appeared to be linearly related but steady-state plasma phenobarbitone levels correlated better with primidone dose than did steady-state plasma levels of primidone itself. This pattern of correlation is probably due to primidone being more rapidly eliminated than the phenobarbitone that is derived from it. Steady-state plasma primidone levels showed more inter-dosage fluctuation than steady-state plasma phenobarbitone levels in the same patients. In the subjects studied age, sex, and concurrent anticonvulsant therapy did not alter the relation between plasma levels of primidone or phenobarbitone and primidone dose. The study suggested that knowledge of steady-state plasma primidone levels adds little to knowledge of plasma phenobarbitone levels in guiding the therapy of epilepsy with primidone.

Two aspects of the correlation of plasma carbamazepine level with drug dose in patients taking carbamazepine tablets indicated the possibility that the drug may be incompletely and variably absorbed from the alimentary tract of man. To investigate this possibility, pharmacokinetic studies were undertaken in six volunteers, who were given increasing single doses of carbamazepine in tablet form at appropriate intervals. These studies gave evidence of slow, and probably incomplete, absorption of carbamazepine. After administration of carbamazepine in a specially-prepared solution to 5 of the subjects, rapid absorption of the drug occurred, and in 4 subjects more drug was absorbed than when the same normal dose was given as tablets. It was concluded that the pharmaceutical formulation of carbamazepine tablets limits the bioavailability of the drug, and that problems may arise if the bioavailability of the drug is to be increased.

Ethosuximide, clonazepam and valproic acid differ in their chemical structures and properties. They appear to be well absorbed when given by mouth, but their patterns of distribution within the body are different. If these 3 drugs have a common mode of action, the virtual restriction of valproate to extracellular water suggests that this common mode of action is likely to involve receptors on the neuronal cell surface. Even if there is no common mode of action the apparent volume of distribution of valproate is consistent with its known effects on enzymes of the GABA shunt, and in particular on those shunt enzymes which are involved in the transmitter GABA pool in the region of synapses. The 3 drugs also show differences in elimination rate, which make it desirable to give valproate 3 times a day and clonazepam twice a day, whereas ethosuximide could reasonably be given once daily without undesirably wide fluctuations in plasma drug level over the dosage interval. Further studies of the pharmacokinetics of ethosuximide, clonazepam and valproate are still needed, but sufficient data are already available to provide some basis for rational use of these drugs in treating petit mal 'absence' epilepsy.

1. Plasma phenytoin (diphenylhydantoin) levels after different drug doses were correlated with urinary 5-(p-hydroxyphenyl)-5-phenylhydantoin (p-HPPH) excretions in four subjects. 2. In three of four subjects the proportion of the phenytoin dose that was excreted as p-HPPH. In the fourth, p-HPPH output remained proportionate to dose of phenytoin until elimination of the drug fell below its input. 3. Plasma p-HPPH levels were measured in two subjects; the data suggested that the renal excretion of p-HPPH was not rate-limited. 4. In three of four subjects, there was the possibility that alternative pathways for eliminating phenytoin may have developed as drug doses increased and the capacity for forming p-HPPH became saturated. 5. Overall phenytoin elimination appeared to approach saturation at concentrations of the drug encountered therapeutically. When Michaelis-Menten kinetics were applied to data for phenytoin elimination in twenty-one adults and fifteen children, the mean apparent Km value for the adults corresponded to a plasma drug concentration of 5-8 mug/ml, and in the children to 5-3 mug/ml. The mean Vmax values in the two groups were, respectively 8-1 mg/kg per day and 12-5 mg/kg per day.

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 the 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 epoxide levels were unaltered. The amount of conversion of carbamazepine to its epoxide thus appears to vary in different circumstances in human.

Plasma aspirin and salicylate levels were measured at intervals over a two hour period during migraine attacks in 10 subjects given 900 mg oral aspirin alone, in 10 subjects given 900 mg oral aspirin plus 10 mg oral metoclopramide, and in 10 subjects given 900 mg oral aspirin plus an intramuscular injection of 10 mg metoclopramide. Higher peak aspirin and salicylate levels occurred in patients given aspirin with metoclopramide. Aspirin tended to appear in plasma earlier in patients given aspirin with oral metoclopramide than in patients given aspirin alone, or aspirin with intramuscular metoclopramide. Patients given aspirin with oral metoclopramide tended to obtain better early pain relief than the other two treatment groups, though by one hour from dosage use of injected metoclopramide was also associated with better pain relief.

A retrospective study of the efficacy of soluble aspirin in migraine has been carried out. Data were available for 61 patients. These patients differed in only relatively minor ways from the remainder of the population of migraine sufferers referred to a neurological consultative practice. Soluble aspirin usually or always relieved migraine attacks in 44% of these patients, and sometimes relieved the disorder in another 25%. Adverse effects mainly nausea and vomiting, were reported by 16% of patients only, and in some cases nausea and vomiting may have been due to migraine rather than to the drug. Response to aspirin was unrelated to factors such as the patient's age, sex and duration of migraine history, and to the severity of migraine or occurrence of nausea and vomiting during attacks. However, the presence of a migraine aura appeared to improve the chances of a response to aspirin. The aura may have permitted earlier recognition that migraine was present, and thus allowed earlier aspirin intake at a stage when it had a better chance of influencing migraine mechanisms.

Anticonvulsant drug interactions have been investigated using multiple linear regression analyses. The one statistically significant interaction found was that in which phenytoin dosage decreased plasma carbamazepine concentrations. There was a suggestion that carbamazepine and phenobarb dosage tended to increase phenytoin levels. No interaction was detected between phenytoin and sulthiame. Studies in individuals suggested that ethosuximide may increase plasma phenytoin concentration and that clonazepam tends to decrease carbamazepine and phenytoin concentrations.

Simultaneous plasma dexamethasone and cortisol levels were followed at intervals over 8 hour periods on 40 occasions in 19 subjects who received regular high dosage dexamethasone therapy (rarely less than 12 mg a day) for various neurological and neurosurgical conditions. Lower dexamethasone doses (for example 2 mg daily for 2 days) normally suppress adrenal cortical production of cortisol to below 50 micrograms/l for at least 8 hours. However, in 12 of the 35 studies that did not take place at the first steroid dose or in subjects taking second daily bolus steroid dosage such suppression was not present 8 to 12 hours after dexamethasone intake, though it was shown that dexamethasone could suppress cortisol production in all these cases. Failure of maintained suppression despite the high steroid dose appeared to be related to rapid elimination of dexamethasone. These findings may help explain the relative rarity of adrenal failure in clinical neurological practice after high dosage steroid therapy is ceased.

A 48 year old man with normal hepatic function presented with abnormally prolonged bleeding following orally administered warfarin. Warfarin and diphenylhydantoin are known to be hydroxylated in the liver. To investigate the possibility of the patient having a metabolic (hydroxylating) defect, his ability to metabolize diphenylhydantoin was studied, as it would have been unethical to administer warfarin again. Parallel studies were carried out on two healthy subjects as a basis for comparison. On three separate occasions the elimination half-life for diphenylhydantoin in the patient (158, 87, 72 hours) was significantly longer than those obtained in the normal subjects (31 and 32 hours). This difference was most probably due to decreased hydroxylation of diphenylhydantoin to 5-(p-hydroxy-phenyl)-5-phenylhydantoin since his urinary elimination of this substance was demonstrated to be significantly less than that of the normal subjects. The results suggest that this patient had a reduced capacity to hydroxylate diphenylhydantoin, and this defect in liver hydroxylation may explain his increased sensitivity to warfarin.

The literature describing drugs assay in plasma and its value for optimal therapy for individual patients is expanding rapidly. The present review seeks to clarify the rationale underlying the assay of plasma concentrations of drugs, and it attempts to define principles for judging the likely value of assaying a particular drug. Examples are given of drugs which are being usefully measured in clinical practice. The most commonly used assay techniques are briefly described, and their principal advantages and limitations are indicated.

The pharmacokinetics of methylphenobarbitone and phenobarbitone were studied following the administration of methylphenobarbitone on a chronic basis in 77 patients, and after a single dose to each of 4 subjects who had received no other drugs and 4 subjects who had been pretreated with various anticonvulsants and other agents. At steady-state, plasma phenobarbitone concentrations correlated better with methylphenobarbitone dose than did plasma methylphenobarbitone concentrations. In this group the ratio of plasma phenobarbitone level to plasma methylphenobarbitone level was in the range of 7 to 10:1. In the single dose studies, mean values of elimination rate constant (0.0155h) and clearance (1.85L/h) for untreated subjects were different from those for the pretreated subjects (0.0375h and 5.10L/h), while the apparent volumes of distribution did not differ significantly between the two groups (120.3L vs 140.8L). The data are interpreted as most probably indicating induction of hepatic microsomal enzymes in the pretreated group.

Cytophotometric measurements of the activities of 5 oxidative enzymes (succinate, malate, lactate, NAD+-linked isocitrate and NADH dehydrogensases) have been made in anterior horn cells of the lumbar and cervical spinal cord of the rabbit. The thickness of tissue sections was measured by an interference microscope and various optical and chemical precautions were taken to diminish the possible errors that might be involved in cytophotometry. The findings of the study indicated a unimodal distribution of the activities of all of the enzymes studied in anterior horn cells, though there was a wide range of enzyme concentration among different cells. Thus the findings in the rabbit are consistent with the "constant proportion" hypothesis of the activity of certain oxidative enzymes, and are contrary to a previous finding that there may be two populations of succinate dehydrogenase-containing anterior horn cell.

Simultaneous steady-state plasma concentrations of carbamazepine and carbamazepine-10,11-epoxide have been measured by high pressure liquid chromatography in 101 epileptic children and adults taking the drug. There was either no statistically significant correlation, or only a very poor correlation, between drug dose and steady-state plasma levels of a) carbamazepine, b) its epoxide, and c) the sum of drug and epoxide. Plasma concentrations of carbamazepine correlated with those of it epoxide. Plasma carbamazepine levels were lower in patients taking phenytoin with carbamazepine than in patients taking carbamazepine alone. Plasma carbamazepine-10,11-epoxide levels were not definitely altered when carbamazepine and phenytoin were used together. This finding is consistent with the hypothesis that phenytoin enhances the metabolism of carbamazepine to a metabolite other than its epoxide.

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.