Kinetics Of Single Oral Doses Research Articles

Single oral dose kinetics of zotepine and its relationship to prolactin response and side effects.

The authors investigated the single oral dose kinetics of zotepine and its relationship with prolactin response and side effects in 14 healthy male volunteers. Each subject took a single oral 25-mg dose of zotepine, and plasma concentrations of zotepine, prolactin, and their side effects were monitored up to 36 hours after dosing. The means +/- SD of the time of maximal plasma concentration (tmax), the apparent oral clearance, the apparent volume of distribution, and the elimination half-life (t1/2) were 3.8 +/- 1.2 hours, 4.6 +/- 4.2 1/h.kg, 109.0 +/- 59.0 1/kg, and 21.0 +/- 8.9 hours, respectively. The change in prolactin concentrations and side effect scores were parallel with that of drug concentrations, although no significant correlation was found between these three parameters at any time-point. The current results clearly indicate that the tmax and t1/2 of zotepine are much longer than those previously reported, which are reflected in the changes in prolactin concentrations and side effect scores.

Ethylmorphine O-deethylation cosegregates with the debrisoquin genetic metabolic polymorphism.

The single oral dose kinetics of ethylmorphine and its fractional metabolic clearance by O-dealkylation and N-dealkylation was investigated in five extensive and four poor metabolizers of dextromethorphan. In addition, the urinary metabolic ratios for these pathways (MRO and MRN, respectively) were investigated in a larger group of 27 extensive metabolizers and six poor metabolizers. The mean values for the fractional metabolic clearance by O-dealkylation and the MRO differed significantly between the poor metabolizers and extensive metabolizers without overlap between the values of either of these parameters in the two groups of subjects. In contrast, the corresponding parameters for the N-demethylation did not differ between poor metabolizers and extensive metabolizers. The area under the plasma concentration versus time curve was significantly higher (about three times higher) in the poor metabolizers compared with the extensive metabolizers (p = 0.004). Our data suggest that ethylmorphine is O-deethylated by the cytochrome P4502D6 isozyme inasmuch as both the fractional metabolic clearance by O-dealkylation and the MRO were found to cosegregate with the phenotype for the O-demethylation of dextromethorphan in our group of subjects.

Effect of Phenobarbital on the Pharmacokinetics of Carbamazepine-10, 11-Epoxide, an Active Metabolite of Carbamazepine

The single oral dose kinetics of carbamazepine-10,11-epoxide (CBZ-E), the active metabolite of carbamazepine, were studied in six epileptic patients, stabilized on phenobarbital (PB) monotherapy, and in six drug-free health volunteers. The epoxide metabolite was administered as an enteric-coated tablet at the dose of 200 mg to the patients and at the dose of 100 mg to the volunteers. Patients had a significantly higher plasma clearance of CBZ-E than the control group (mean values +/- SD = 220.2 +/- 63.5 versus 112.5 +/- 46.0 ml/h/kg, p less than 0.007) and a significantly shorter plasma half-life (mean values +/- SD = 4.3 +/- 1.0 versus 6.7 +/- 0.8 h, p less than 0.0015). These results suggest that PB induces CBZ-E metabolism.

Lack of effect of cimetidine on pharmacodynamics and kinetics of single oral doses of R- and S-acenocoumarol.

The kinetics and dynamics of single doses (5 mg p.o.) of the optical isomers of acenocoumarol (R-AC and S-AC) were followed in healthy subjects and the effect on them of cimetidine 800 mg/day was also investigated. The AC enantiomers differed greatly in their pharmacokinetics. The mean residence time (MRT) of R-AC was about 10 times longer than that of S-AC, 15 h vs 1.2 h. There was no difference in the volume of distribution. Depression of blood clotting activity (Thrombotest) was observed only after administration of R-AC. The inactivity of S-AC as a vitamin K antagonist must be ascribed to its short MRT. Cimetidine did not affect the acute oral kinetics of R- and S-AC, nor did it affect the anticlotting activity of R-AC. The urinary excretion pattern of the 6- and 7-hydroxylated AC metabolites was not altered during cimetidine treatment. Although the present studies showed no effect of cimetidine on the pharmacokinetics and dynamics of acenocoumarol, the findings of Serlin et al. suggest that cimetidine should not be administered during acenocoumarol therapy.

Interaction of cimetidine with oxazepam, lorazepam, and flurazepam.

The influence of cimetidine coadministration, 300 mg every 6 hours, on the kinetics of single oral doses of oxazepam (30 mg), lorazepam (2 mg), and flurazepam (30 mg) was evaluated in healthy volunteers. Cimetidine had no significant effect on the peak plasma concentration or the time of peak concentration for either oxazepam, lorazepam, or desalkylflurazepam (formed from flurazepam). Cimetidine likewise did not alter the elimination half-life of oxazepam (9.4 hours) or lorazepam (11.6 hours), and did not change total AUC for lorazepam. Oxazepam AUC was increased an average of 10 per cent by cimetidine (P less than 0.02). In contrast, cimetidine prolonged desalkylflurazepam elimination half-life (141 vs. 94 hours, P less than 0.1) and increased AUC an average of 65 per cent (P less than 0.05). Thus, cimetidine has little or no influence on the absorption or disposition of oxazepam and lorazepam, two benzodiazepines biotransformed by glucuronide conjugation. However, cimetidine slows the elimination of flurazepam's metabolite, desalkylflurazepam, which is biotransformed by oxidation.

The debrisoquine hydroxylation test predicts steady-state plasma levels of desipramine.

British Journal of Clinical PharmacologyVolume 15, Issue 3 p. 388-390 Free Access The debrisoquine hydroxylation test predicts steady-state plasma levels of desipramine. L Bertilsson, L BertilssonSearch for more papers by this authorA Aberg-Wistedt, A Aberg-WistedtSearch for more papers by this author L Bertilsson, L BertilssonSearch for more papers by this authorA Aberg-Wistedt, A Aberg-WistedtSearch for more papers by this author First published: March 1983 https://doi.org/10.1111/j.1365-2125.1983.tb01518.xCitations: 66AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References ABERG-WISTEDT, A. (1982). A double-blind study of zimelidine, a serotonin uptake inhibitor, and desipramine, a noradrenaline uptake inhibitor in endogenous depression. I. Clinical findings. Acta Psychiat. Scand., 66, 50– 65. ALEXANDERSON, B. (1972). Pharmacokinetics of desmethylimpramine and nortriptyline in man after single and multiple oral doses—A cross-over study. Eur. J. clin. Pharmac., 5, 1– 10. ALEXANDERSON, B. (1973). Prediction of steady-state plasma levels of nortriptyline from single oral dose kinetics: A study in twins. Eur. J. clin. Pharmac., 6, 44– 53. BERTILSSON, L., DENGLER, H.J., EICHELBAUM, M. & SCHULZ, H.-U. (1980). Pharmacogenetic covariation of defective N-oxidation of sparteine and 4-hydroxylation of debrisoquine. Eur. J. clin. Pharmac., 17, 153– 155. HAMMER, W. & SJOQVIST, F. (1967). Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine-like compounds. Life Sci., 6, 1895– 1903. HAMMER, W., MARTENS, S. & SJÖQVIST, F. (1969). A comparative study of the metabolism of desmethylimi-pramine, nortriptyline and oxyphenylbutazone in man. Clin. Pharmac. Ther., 10, 44– 49. MAHGOUB, A., IDLE, J.R., DRING, L.G., LANCASTER, R. & SMITH, R.L. (1977). Polymorphic hydroxylation of debrisoquine in man. Lancet, ii, 584– 586. MELLSTRÖM, B., BERTILSSON, L., SÄWE, J., SCHULZ, H.-U. & SJOQVIST, F. (1981). E- and Z-10-hydroxylation of nortriptyline: Relationship to polymorphic debrisoquine hydroxylation. Clin. Pharmac. Ther., 30, 189– 193. POTTER, W.Z., BERTILSSON, L. & SJÖQVIST, F. (1981). Clinical pharmacokinetics of psychotropic drugs: Fundamental and practical aspects. In Handbook of Biological Psychiatry, VI, eds H. Praag, M.H. Lader, O.J. Rafaelsen & E.J. Sachar, pp 71– 134. New York: Marcel Dekker Inc. POTTER, W.Z., CALIL, H.M., SUTFIN, T.A., ZAVADIL, A.P., JUSKO, W.J., RAPOPORT, J. & GOODWIN, F.K. (1982). Active metabolites of imipramine and desipramine in man. Clin. Pharmac. Ther., 31, 393– 401. Citing Literature Volume15, Issue3March 1983Pages 388-390 ReferencesRelatedInformation

Nortriptyline metabolism in chronic renal failure: metabolite elimination.

Single oral dose kinetics of nortriptyline and of tis two major metabolites, conjugated and unconjugated 20-hydroxynortriptyline, were studied in eight healthy subjects and 15 patients with chronic renal failure, five of whom were being treated with hemodialysis. Nortriptyline kinetics were unaltered, but the elimination of the metabolites was reduced in both groups of patients. In chronic renal failure the excretion of nortriptyline metabolites appeared to be the rate-limiting step in nortriptyline elimination. Three depressed hemodialysis patients were treated with nortriptyline (75 mg at night) for 6 wk. The ratios of the steady-state plasma concentrations of unconjugated 10-hydroxynortriptyline to nortriptyline (0.74 to 2.30) were in the same range as those in a control group of depressed patients with adequate renal function (0.53 to 4.08) who were also receiving nortriptyline. Conjugated 10-hydroxynortriptyline in renal failure patients was slow to reach steady-state concentrations and these were 10 to 20 times as high as those of the control depressed patients. Conjugated 10-hydroxynortriptyline in dialysis fluid during treatment showed that a mean 43 +/- 7% (SD) of the dose was removed by a 10-hr dialysis. Dialysis clearance of conjugated 10-hydroxynortriptyline was 58 +/- 8 (SD) ml min-1, but nortriptyline and unconjugated 10-hydroxynortriptyline were not appreciably removed by dialysis. Hemodialysis is not likely to be of value in the management of acute nortriptyline poisoning.

Clonidine kinetics in man--evidence for dose dependency and changed pharmacokinetics during chronic therapy.

1 Clonidine kinetics were studied in 21 patients with essential hypertension. All received two bolus i.v. injections in the mean dose range of (0.78--3.36 micrograms kg-1) and one single oral dose (mean dose 1.7--2.3 micrograms kg-1) on separate occasions. The kinetics were also studied in some of these patients after multiple therapeutic oral dose (mean dose 1.1 or 1.9 micrograms kg-1) twice daily during a dosage interval after 6--12 months monotherapy with clonidine. The multiple oral dosage was based on the therapeutic response. 2 With increasing i.v. doses the rate constants (alpha, beta) decreased and the plasma clearance was reduced by 74% (9.94--2.61 ml min-1 kg-1) indicating dose-dependent kinetics. The volume of distribution (Vd beta) did not change with dose in contrast to the volume of the plasma compartment (Vc) which was increased at the highest doses. 3 The single oral dose kinetics agreed with the i.v. kinetics at comparable dose. The bioavailability was 90%. 4 During multiple oral dosing the elimination rate constants decreased compared to the single dose. The plasma clearance increased (7.18 ml min-1 kg-1) compared to the corresponding single dose (4.17 ml min-1 kg-1). The latter change was probably caused by the decrease in bioavailability to about 65%. 5 The pharmacodynamic properties of the drug could explain the changes in pharmacokinetics with increased dose and during multiple doses.

Prediction of steady-state plasma levels of nortriptyline from single oral dose kinetics: a study in twins.

Five identical (monozygotic) and 6 fraternal (dizygotic) sets of healthy twins between 47 and 53 years of age were given a single oral dose of nortriptyline (NT) hydrochloride 1 mg/kg. The plasma half-life, the apparent volume of distribution, and the plasma clearance of NT were estimated for each subject as well as the urinary excretion rate of conjugated and unconjugated 10-hydroxynortriptyline (10-OH-NT). “Steady-state” plasma levels predicted from the reciprocal single dose plasma clearance rate of NT agreed well with those observed in a previous study of the same twins 2 years previously. In the present study, there was a 5-fold range of the plasma half-lives and 2-fold variation in the apparent volume of distribution of NT (assuming complete availability on oral administration). No correlation was found between the plasma half-life and the apparent volume of distribution. Analysis of variance showed that most of the variability between persons in plasma half-life, apparent volume of distribution and conjugation of 10-OH-NT was genetically determined. The plasma half-life and apparent volume of distribution may contribute independently to the total interindividual variability of the “steady-state” plasma level of NT.