A study of the pharmacokinetics and pharmacodynamics of nifedipine in combination with atenolol.

This double-blind randomized, crossover study was undertaken to determine the pharmacokinetic properties of nifedipine retard and atenolol when given separately, as a free or a fixed combination, compared with placebo in 15 healthy male volunteers. There was no difference between the three atenolol formulations in time to maximum blood concentration or elimination half-life. The fixed combination showed significant differences in both maximum observed blood concentrations (+16 per cent) and total area under the curve (+16 per cent) compared to atenolol alone. Urinary recovery of unchanged drug from the fixed combination was also slightly increased but the difference was not statistically significant. Furthermore, statistical evaluation of the plasma pharmacokinetics of nifedipine retard and urinary recovery of nifedipine metabolite showed that all three formulations were indistinguishable. Thus, it is concluded that the fixed combination of nifedipine and atenolol is bioequivalent to the free combination and that the bioavailability of both drugs in the fixed combination is equivalent to that of the single entities.

The effect of ageing on the disposition of nifedipine and atenolol.

1. Healthy young and elderly volunteers received 20 mg nifedipine (slow release) orally for 2 weeks with concomitant dosing of atenolol 50 mg orally during the second week. 2. Drug kinetics and dynamics were compared between the groups after a single dose of nifedipine (day 1), after chronic dosing for 1 week (day 8), and following concomitant daily dosing of atenolol (day 15). 3. Plasma profiles of nifedipine were similar within each group on each of the 3 sampling days. The elderly group had higher plasma concentrations from about 6 h but there was no difference in the maximum concentrations achieved. The half-life in the elderly was significantly longer (8.8 +/- 0.9 h) compared with that in the young (5.8 +/- 1.1 h) (P less than 0.01). 4. Blood concentrations of atenolol were higher in the elderly at 12 and 24 h post-dose (P less than 0.001) and the AUC was greater than in the young (P less than 0.001). 5. Systolic blood pressure was reduced by nifedipine in both groups but to a greater extent in the elderly (P less than 0.01); differences in diastolic blood pressure were not significant. Blood pressure was reduced further by the addition of atenolol. Atenolol reduced the heart rate in all subjects.

A comparative study of the pharmacokinetics and pharmacodynamics of atenolol, hydrochlorothiazide and amiloride in normal young and elderly subjects and elderly hypertensive patients.

Six normal young and six normal elderly volunteers and six elderly hypertensive patients took part in an acute and chronic dose study of a combination capsule containing atenolol (50 mg), hydrochlorothiazide (25 mg) and amiloride (2.5 mg) designed for the treatment of hypertension. No difference in any of the drug pharmacokinetic parameters could be detected between the hypertensives and the normal elderly subjects. The bio-availability and the 24-h blood concentrations of all three drugs, half-life of atenolol and amiloride and the peak concentration of hydrochlorothiazide was significantly greater in the elderly. The 24-h blood concentrations of atenolol and hydrochlorothiazide did not alter with chronic dosing, but amiloride concentrations were significantly higher at this time in all groups. A significant fall in the blood pressure was observed in the hypertensive group. Heart rate fell more in the normal and hypertensive elderly subjects than in the young. The combination has shown to be an effective and well tolerated antihypertensive in the elderly patient with a 24-h duration of action.

Clobuzarit: species differences in the morphological and biochemical response of the liver following chronic administration.

Clobuzarit is structurally related to a number of hypolipidemic agents which produce characteristic changes in rodent liver morphology and biochemistry. Liver effects were determined in a number of rodents, the albino rat, C57BL/10J mouse, and Syrian hamster, and in other mammals, the beagle dog and marmoset monkey, following chronic (14-day) oral administration of clobuzarit at two dose levels. Expected (peak) serum levels of clobuzarit were achieved in all species except the marmoset in which levels were approximately half those predicted. Dose-dependent enlargement of rat and mouse liver cells (assessed qualitatively by light microscopy) was observed. This finding was accompanied by proliferation of peroxisomes and smooth endoplasmic reticulum (assessed by electron microscopy and enzymatically). In the rat and mouse, the fatty acid oxidation enzyme systems of peroxisomes and endoplasmic reticulum were markedly induced. The hamster showed no increase in liver cell size but there was a limited proliferation of peroxisomes (indicated by electron microscopy and enzymatically) and an increase in endoplasmic reticulum fatty acid oxidase. No proliferative effects were observed in the liver of the dog or marmoset. Lowering of plasma triglycerides and cholesterol was observed in the rat only. The differences in the morphological and biochemical responses to clobuzarit among the species used in this toxicity testing clearly illustrate the problems of predicting effects in man from animal data.

Identification and biological activity of tamoxifen metabolites in human serum.

During the examination of serum samples from patients on chronic 'Nolvadex' therapy three major metabolites (X, Y and Z) were detected in addition to the parent drug. Two of these metabolites have been positively identified as N-desmethyltamoxifen (X) and a side-chain primary alcohol (Y). The third metabolite (Z) has been tentatively identified as N-desdimethyltamoxifen. Quantitative analysis of these metabolites in sera from patients undergoing chronic Nolvadex therapy (20 mg approximately b.d.) has shown that the mean N-desmethyltamoxifen concentration was 481 ng/ml, the mean metabolite Y concentration was 49 ng/ml and that desdimethyltamoxifen concentrations were in the range 20-40 ng/ml. The corresponding mean unchanged drug level in these patients was 310 ng/ml. 4-Hydroxytamoxifen could not be detected in these samples. Measurements of the relative binding affinities of tamoxifen and its metabolites for rat uterus oestrogen receptors have shown that 4-hydroxytamoxifen had a relative binding affinity similar to oestradiol while tamoxifen and its side-chain metabolites had lower affinities. It has been shown that all the metabolites examined are antioestrogenic, as demonstrated by their ability to prevent implantation in pregnant rats and inhibit oestradiol-induced uterine weight gain. It is therefore possible that the metabolites of tamoxifen collectively contribute to the therapeutic activity of the drug.

Pharmacokinetic evaluation of ICI 35 868 in man. Single induction doses with different rates of injection.

Blood concentrations of ICI 35 868 have been measured in patients following a single bolus dose of 2 mg kg-1. Three different rates of injection of the anaesthetic agent (3-5s, 20s and 40 or 50s) were examined. Pharmacokinetic indices, derived from blood concentrations of ICI 35 868, were independent of the speed of injection. The blood profiles could be described by a two-compartment open model with a mean alpha-phase half-life of 2.5 min and a mean beta-phase half-life of 54.5 min. The mean total body clearance was 3454 ml min-1. Similar data were obtained from a 4-mg kg-1 dose. The mean recovery time (4.4 min) and concentration of ICI 35 868 at awakening (1.05 micrograms ml-1) were also independent of the rate of injection. Using the derived pharmacokinetic model, predictions of drug concentrations have been made for repeated bolus doses, or infusions, of ICI 35 868.

Pharmacokinetics and tolerance of single intravenous doses of cefotetan disodium in male Caucasian volunteers.

Cefotetan, a third generation cephalosporin, in doses of 0.25, 0.5, 1.0 and 2.0 g was administered intravenously as the disodium salt to ten healthy male Caucasian volunteers and its pharmacokinetics and tolerance determined. The elimination half-life was 3.3 h. The drug was 88% plasma protein bound and 67% was recovered unchanged in the urine. HPLC and bioassay techniques for cefotetan plasma-concentration determinations gave virtually identical results. Cefotetan was well tolerated although half of the volunteers experienced transient mild to moderate diarrhoea. It is concluded that the pharmacokinetic disposition of cefotetan is similar in Caucasian and Japanese subjects and that the long elimination half-life, lack of detectable metabolism and high urinary excretion will result in plasma and urine concentrations in excess of the MIC of sensitive bacteria on a twice daily dosing regime.

Pharmacokinetics and tolerance of a 24-h infusion of cefotetan disodium (with and without loading dose) in normal Caucasian volunteers.

Cefotetan disodium has been given by zero order intravenous infusion at 75.8 mg/h to four healthy male volunteers over a 24-h period. Plasma concentrations rose until by 12 hs a mean steady state value of 37.5 mg/l was attained. In an additional four volunteers a loading dose of 0.5 g cefotetan was given immediately prior to a similar infusion. In these subjects concentrations in excess of the final steady-state value of 36.2 mg/l were achieved immediately and concentrations never fell below this value for the entire 24-h period of the study. The dose was well tolerated with the exception of an incidence of diarrhoea (2/8 mild and 1/8 severe). The pharmacokinetic findings are in good agreement with theoretical predictions based on single intravenous bolus doses of cefotetan and suggest that a loading dose, followed by an infusion would be suitable regime for cases of severe infection.

Blood disoprofol levels in anesthetised patients. Correlation of concentrations after single or repeated doses with hypnotic activity.

The blood concentrations of disoprofol (Diprivan) after single intravenous doses of 1, 2 or 3 mg/kg have been examined in a subpopulation from previously reported clinical studies. The linear relationship between sleep time and dose could be explained by the linearity of the pharmacokinetics at these doses. After a single injection the awakening concentration was independent of dose, with a mean value of 1.04 micrograms/ml. No acute tolerance occurred with disoprofol. On repeated 1 mg/kg bolus injections the sleeping time rose initially but stabilised after four doses. The waking concentration was independent of the number of doses administered. The clinical findings fitted an agent with a very rapid distribution phase and a short elimination half-life.

Anticonvulsant and proconvulsant properties of viloxazine hydrochloride: pharmacological and pharmacokinetic studies in rodents and the epileptic baboon.

Viloxazine HCl is evaluated as an anticonvulsant in a wide range of rodent seizure models and in the epileptic baboon (Papio papio). In the maximal electroshock test, the oral ED50 for abolition of tonic extension was 9 mg/kg-1 after 30-min pretreatment (mouse) rising to 30 mg/kg-1 after 60 min (mouse and rat). Comparable ED50 values were also found for protection against tonic extension in the mouse induced by the administration of the chemical convulsants metrazole or 3-mercaptopropionic acid. In DBA/2 mice the ED50 for abolition of tonic extension during sound-induced seizures was 6.8 mg/kg-1 IP (30-min pretreatment). Pharmacokinetic studies in the mouse showed peak plasma levels to occur 30 min following oral doses, with a mean half-life of 58 min. The anticonvulsant plasma concentration was within 0.5 -- 1 microgram/ml-1. In the baboon, significant protection against photomyoclonic responses is observed 1 -- 2h after viloxazine (2.6 mg/kg-1 IV), during which period the plasma concentration was again 0.5-1 microgram/ml-1. After administration of approximately ten-times this latter dose level, i.e. 24 mg/kg-1 IV, a syndrome characterised by an abnormal EEG and, in some instances, seizure activity was observed.

Pharmacokinetics in laboratory animals of ICI 35 868, a new i.v. anaesthetic agent.

Blood concentrations of ICI 35 868 have been determined in rat, pig, rabbit and cat after single i.v. injections. In all species the initial distribution volume was greater than blood volume and the overall distribution volume was large. Half-lives of the distribution phase were extremely short (1-6 min) and the terminal half-lives were also short (16-55 min). In all species examined a correlation existed between the systemic blood concentration of ICI 35 868 and duration of sleep, with concentrations in the range 1-4 micrograms ml-1 being effective in producing unconsciousness. No changes in pharmacokinetics or in the effective concentration occurred on repeated administration or after infusion.

Studies on the metabolism and pharmacokinetics of tamoxifen in normal volunteers.

The densitometric analytic procedure used for tamoxifen can also be used to quantify its desmethyl metabolite. In a study involving six healthy male volunteers, tamoxifen tablets were shown to be as bioavailable as a solution of tamoxifen citrate. After administration of a single dose of 20 mg, peak serum levels of tamoxifen were 42 ng/ml; those of the metabolite were 12 ng/ml. The half-lives of the drug and metabolite were approximately 4 and 9 days, respectively, after a single dose. After three widely separated single doses, a reversible increase in elimination half-life occurred.

Measurement of tamoxifen in serum by thin-layer densitometry.

A method is described for the determination of tamoxifen in serum. The drug was extracted from the serum and separated from its metabolites by thin-layer chromatography. Irradiation of the thin-layer plate with ultra-violet light after development converted tamoxifen to a fluorescent product which could be estimated in situ by densitometry. The fluorescent product was identified as a substituted phenanthrene by thin-layer chromatography, and gas chromatography--mass spectrometry. The method allowed concentrations as low as 6.8 nmol/l serum to be measured. After an oral dose of tamoxifen (10 mg) to a female patient the maximum serum concentration (66.2 nmol/l) was achieved in 3 h. When 10 mg tamoxifen were taken twice daily for 21 days by the same patient serum concentrations of about 500 nmol/l were achieved.

Relationship between blood and cerebrospinal levels of the antidepressant agent viloxazine.

Viloxazine levels in blood and CSF have been measured following acute and chronic dosing in depressed patients. Blood profiles confirm previous findings that viloxazine is rapidly absorbed and eliminated with a half-life of 4.5 h. Viloxazine crosses the blood-brain barrier and concentrations in CSF remain virtually unchanged over a ten hour period post administration. Viloxazine does not accumulate in CSF on chronic administration. The fact that CSF levels do not reflect concentrations in blood has significant implications on any attempt to correlate the clinical efficacy and the pharmacokinetic behaviour of an antidepressant agent.