Chronopharmacokinetic and bioequivalence studies of two formulations of trimipramine after oral administration in man

The temporal variations in the pharmacokinetics and pharmacodynamics of methylprednisolone at 8 AM versus 4 PM were investigated in six healthy male volunteers. Subjects completed three phases: no drug administration, 20 mg intravenous methylprednisolone at 8 AM, and the same dose at 4 PM. Methylprednisolone clearance was 28% greater in the afternoon. The suppressive effects of methylprednisolone on basophils (measured as whole blood histamine), helper T lymphocytes, and cortisol concentrations, assessed by the ratio of the area under the curve (AUC) after methylprednisolone to the baseline AUC, were not different between the phases. The 50% inhibitory concentration values for methylprednisolone derived from pharmacodynamic models were also similar, indicating no difference in intrinsic responsiveness. However, cortisol concentrations returned to baseline about 4 hours earlier after the 4 PM compared with the 8 AM dose because of the enhanced afternoon methylprednisolonc clearance. These findings are in agreement with other studies that suggest adequate clinical effects and less disturbance of cortisol circadian behavior when methylprednisolone is administered as a single dose in the morning.Corticosteroids are an important class of therapeutic agents because of their antiinflammatory and immuno-suppressive properties. Ideal dosing regimens have yet to be elucidated for the treatment of numerous disease states. Currently, corticosteroids are most often administered as a single morning dose. However, these agents may be administered as divided doses or even as a single evening dose in those conditions requiring adrenal suppression. 1 Numerous drugs, including theophylline, 2 phenyloin, 3 and cisplatin, 4 have demonstrated temporal variations in their pharmacokinetics. This is not surprising because it has been shown in animals that both hepatic drug-metabolizing activities and renal clearance (CL R ) mechanisms exhibit circadian variations. 5,6 Human chronopharmacokinetic studies with exogenous corticosteroids are limited. Prednisolone has been evaluated in three studies with conflicting findings. The first study 7 found no circadian differences in prednisolone Copyright © 1992 clearance, volume of distribution (V), or half-life (t ½ ). The second study 8 found circadian differences in the clearance (CL) of free prednisolone and the free fraction when it was given as a low dose. The third study 9 found circadian variation in all parameters investigated. To date, no human chronopharmacokinetic study with methylprednisolone has been reported. In male Norwegian rats, the maximum methylprednisolone t ½ was noted to occur when the drug was administered at 6 PM, the commencement of the nocturnal activity period of the animals, whereas the shortest t ½ was documented with noon administration, or midway through the diurnal rest span. 10 The pharmacodynamics of exogenous corticosteroids may show temporal variations. The susceptibility of the hypothalamic-pituitary-adrenal axis to suppression in humans, as measured...

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“…[30][31][32][33][34] Our finding of no difference in disposition of the highly cleared pro-drug MPS is consistent with these studies.…”

Section: Discussionsupporting

confidence: 90%

Pharmacokinetics and pharmacodynamics of methylprednisolone when administered at 8 AM versus 4 PM

Fisher

Ludwig

Wald

et al. 1992

Clin Pharmacol Ther

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“…Various drugs show dosing time-dependent pharmacokinetics [23333435]. Imipramine is metabolized to desipramine by CYP1A2, 3A4, and 2C19, and imipramine and desipramine are hydroxylated to the 2-OH form by CYP2D6 [3637].…”

Section: Discussionmentioning

confidence: 99%

Time of Administration of Acute or Chronic Doses of Imipramine Affects its Antidepressant Action in Rats

Kawai¹,

Kodaira²,

Tanaka³

et al. 2018

Journal of Circadian Rhythms

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The pathogenesis and therapeutics of depression are linked to the operation of the circadian system. Here, we studied the chronopharmacological action of a tricyclic antidepressant, imipramine. Male adult Wistar–Hannover rats were administered imipramine acutely or chronically in the morning or in the evening. The antidepressant action of imipramine was analyzed using the forced swim test (FST). A single dose of imipramine (30 mg/kg) in the morning, but not in the evening, reduced immobility and increased climbing in the FST. The plasma concentrations of imipramine and its metabolite, desipramine, were slightly higher in the morning than in the evening, which might explain the dosing time-dependent action of imipramine. Next, we analyzed the effect of chronic imipramine treatment. Rats received imipramine in the morning or in the evening for 2 weeks. The morning treatment resulted in larger effects in the FST than the evening treatment, and was effective at a dose that was ineffective when administered acutely. The levels of brain α-adrenergic receptors tended to decrease after chronic imipramine treatment. Imipramine might interact with noradrenergic neurons, and this interaction might chronically alter receptor expression. This alteration seemed greater in the morning than in the evening, which might explain the dosing time-dependent action of imipramine.

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“…20) However, there are few reports on the mechanism of the chronopharmacological activity of antidepressants, and the effects of other neural systems such as the noradrenergic system remain to be clarified. Since clinical studies have suggested that different drugs show different chronopharmacological profiles, [21][22][23][24] it is important to analyze various drugs with different mechanisms of action. In this study, we attempted to determine the effects of dosing time on the activity of the dual-action SNRI milnacipran with the use of the modified FST, and we analyzed the mechanism underlying milnacipran's chronopharmacological action.…”

mentioning

confidence: 99%

Chronopharmacological Analysis of Antidepressant Activity of a Dual-Action Serotonin Noradrenaline Reuptake Inhibitor (SNRI), Milnacipran, in Rats

Kawai

Machida

Ishibashi

et al. 2018

Biological & Pharmaceutical Bulletin

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Biological rhythms are thought to be related to the pathogenesis and therapy of various diseases including depression. Here we investigated the influence of circadian rhythms on the antidepressant activity of the dual-action serotonin-noradrenaline reuptake inhibitor (SNRI) milnacipran. Rats administered milnacipran in the morning (8:00 a.m.; zeitgeber time [ZT]1) or in the evening (8:00 p.m.; ZT13) were analyzed in a forced swim test (FST). At ZT1, the rats' immobility was reduced and the swimming was increased, whereas at ZT13, their climbing was increased. These results suggest that the serotonergic and noradrenergic systems are preferentially affected at ZT1 and ZT13, respectively by milnacipran. We analyzed the plasma and brain levels of milnacipran after administration, and there were no differences between ZT1 and ZT13. The circadian rhythm of monoamine neurotransmitters was analyzed in several brain regions. The serotonin turnover showed rhythms with a peak during ZT18-ZT22 in hippocampus. The noradrenaline turnover showed rhythms with a peak during ZT22-ZT2. There was a difference of approx. 4 h between the serotonergic and noradrenergic systems. This time difference might be one of the factors that affect the action of milnacipran and contribute to the dosing time-dependent behavioral pattern in the FST.Key words circadian rhythm; antidepressant; forced swim test; milnacipran; serotonin; noradrenaline Many physiological functions have a rhythm with a period of 24 h. In mammals, circadian clock systems govern almost all organs, and they affect the pathophysiology of various diseases such as cancer, cardiovascular diseases, and psychiatric diseases.1-4) The circadian clock systems also affect the efficacy of medication by influencing the pharmacokinetics and/or pharmacodynamics of the drug.5-7) The efficacy of various drugs varies according to the dosing time.8) It is important to consider the chronopharmacological profiles of each drug in order to provide effective medication.Depression is one of the diseases thought to be affected by the circadian system. Depressive symptoms relate to the chronotype, 9) the symptoms of the depression show diurnal variations, 10) certain types of depression are developed according to the length of daylight, 11) and the modification of the circadian systems is sometimes effective for treating patients.12-14) The monoamine hypothesis proposes that the reduction of monoamine systems in the brain causes depression. However, the interactions between the circadian system and various pathophysiologies are not yet thoroughly understood.Many therapeutic drugs have been developed for depression, and various drugs such as tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotoninnoradrenaline reuptake inhibitors (SNRIs) are currently used in clinical settings. Most of these drugs modify the monoaminergic systems in the brain to exert their antidepressant activity.In rodent models used to assess the effectiveness of antidepressants, the forced swim te...

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Chronopharmacokinetic and bioequivalence studies of two formulations of trimipramine after oral administration in man

Cited by 8 publications

References 11 publications

Pharmacokinetics and pharmacodynamics of methylprednisolone when administered at 8 AM versus 4 PM

Pharmacokinetics and pharmacodynamics of methylprednisolone when administered at 8 AM versus 4 PM

Time of Administration of Acute or Chronic Doses of Imipramine Affects its Antidepressant Action in Rats

Chronopharmacological Analysis of Antidepressant Activity of a Dual-Action Serotonin Noradrenaline Reuptake Inhibitor (SNRI), Milnacipran, in Rats

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