Variation In Steady-state Concentrations Research Articles

Therapeutic monitoring of psychoactive drugs - antidepressants: A review

Major depression, is one of the most prevalent mental disorders in Europe and the USA. The dramatic rise in pharmacological antidepressants is mainly due to increase in use of selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors and other new generation antidepressants. In clinical practice, optimum individual doses are often guided by trial-and-error. This article reviews the available literature on therapeutic monitoring of antidepressant drugs. A search using MEDLINE (english-language reports, 1983 - August 2012) with the key words for antidepressant drugs and therapeutic drug monitoring. There is a need for monitoring antidepressants due to wide interindividual pharmacokinetic variability. At the same drug dose, a more than 20-fold variation in steady state concentration of drug in the body may result: people differ in their ability to absorb, distribute, metabolise and excrete drugs for reasons of concurrent disease, age, gender, smoking and eating habits, concomitant medication and genetics. Monitoring of antidepressant drugs enables us to individualise drug doses based on rational therapy, minimalise side effects, reduce morbidity and mortality and cut the cost of health care. Phenotyping and genotyping could increase therapeutic drug monitoring furthere.

Phenotyping and Genotyping of Drug Metabolism to Guide Pharmacotherapy in Psychiatry

In psychiatry, around 130 drugs are available which have been detected and developed during the last 60 years. These drugs are effective and essential for the treatment of many psychiatric disorders and symptoms. Therapeutic outcomes, however, are still far from satisfactory for many patients. One major reason underlying insufficient response or problems of tolerability or toxicity is considerable interindividual variability in the pharmacokinetic properties of the patients. At the exact same dose, a more than 20-fold interindividual variation in steady state concentrations of the drugs in the body may result. Patients differ in their ability to absorb, distribute, metabolize and excrete drugs due to concurrent disease, age, concomitant medication or genetic peculiarities. A valuable tool for tailoring the dosage of the prescribed medication(s) to the individual characteristics of a patient is therapeutic drug monitoring (TDM). For a considerable number of psychopharmacologic compounds, TDM has become a clinical routine for dose adjustment. The benefits of TDM regarding optimization of psychopharmacotherapy can be further enhanced by genotyping of cytochrome P450 enzymes (CYP). These enzymes are highly polymorphic and involved in the metabolism of most psychotherapeutic drugs. Genotyping related information may be supportive especially for drugs that are predominantly metabolized by CYP2C19 or CYP2D6. The in vivo activity of CYP isoenzymes can be determined using probe drug assays. When used appropriately, phenotyping and genotyping methods are most helpful for problem solving and improvement of the outcomes of psychopharmacotherapy for many patients.

Pharmacokinetics of the selective serotonin reuptake inhibitor paroxetine: nonlinearity and relation to the sparteine oxidation polymorphism.

Steady-state plasma concentrations of paroxetine were studied at five or more paroxetine dose levels (10 to 70 mg/day) in each of 13 extensive metabolizers of sparteine and at three or four dose levels (10 to 40 mg/day) in each of three poor metabolizers of sparteine, all treated for diabetic neuropathy symptoms. On a dose of 30 mg/day there was a 25-fold variation in steady-state concentrations (25 to 670 nmol/L). The upper extreme of this variation was made up by the poor metabolizers of sparteine and the lower extreme by some fast extensive metabolizers. Further, within the extensive metabolizer group, steady-state levels showed a significant, positive correlation with sparteine metabolic ratio at all dose levels. On increasing doses, a disproportionate increase in plasma drug levels was observed in the majority of patients. In nearly all extensive metabolizers the concentration-dose data were best described by a pharmacokinetic model assuming elimination by at least two kinetically distinct processes, one a high-affinity saturable process and one a low-affinity linear process. Estimates of clearance at low drug levels of the high-affinity process showed a significant negative correlation with the sparteine metabolic ratio. Clearance of the low-affinity process was not related to the metabolic ratio and was of the same magnitude in extensive and poor metabolizers. The data thus confirmed that the metabolism of paroxetine and sparteine cosegregates and indicated that the enzyme responsible for a high-affinity saturable paroxetine elimination process is identical with CYP2D6, the source of the sparteine oxidation polymorphism.

Imipramine: A model substance in pharmacokinetic research

The pharmacokinetics of imipramine have been studied over a period of 20 years. Imipramine is rapidly and almost completely metabolized with the formation of desipramine (desmethylation), 2-hydroxy metabolites and subsequent glucoronide coupling. Imipramine has a high clearance (0.8-1.5 l/min) and a corresponding high first pass elimination (30-70%). Volume of distribution is high (650-1100 1) and half-lives accordingly of medium length (6-12 h). The 2-hydroxylation which is the most important step of elimination is mediated via microsomal cytochrome P450 isozyme that exhibit monogenetic polymorphism such that 5-10% of the population have a severely reduced clearance. Co-administration of neuroleptics may also considerably impair the 2-hydroxylation. Steady-state levels of imipramine and desipramine varies considerably among individuals mainly due to variations in metabolism, but also to a smaller extent due to variations in binding to plasma proteins. The variations in steady-state concentrations appear to have clear implication for the clinical effects of imipramine.

Comparative pharmacokinetics of zimelidine and desipramine in man following acute and chronic administration

Single dose and steady-state pharmacokinetics of zimelidine and desipramine were compared in eight depressed patients who were subjects in a double-blind crossover study. Within the same patient, there was no relationship between the pharmacokinetics of desipramine (pharmacokinetically similar to all other tricyclic antidepressants) and those of zimelidine, a bicyclic antidepressant. The weight-corrected dose of zimelidine gives a reasonable index of the concentration of its active metabolite norzimelidine, which predominates over zimelidine by a ratio of approximately 3 to 1. The variation in steady-state concentration of norzimelidine for a given dose of zimelidine in adults is about twofold and can be reduced by correcting for weight.

Single and multiple dose pharmacokinetics of pindolol.

The pharmacokinetics of pindolol were studied in six healthy individuals following a single 10 mg dose (SD) and multiple (5 mg tid over 6 days) dose (MD). The plasma elimination half-life was identical after SD (4.7 +/- 0,8h) and MD (4.1 +/- 1.1h). Steady state plasma concentrations were reached after 36 h and remained stable thereafter. The variation in steady state concentrations was small in each individual and also between individuals. The steady state concentration of pindolol can be predicted from the pharmacokinetic data obtained after a single dose. The results of the present study suggest that the disposition of pindolol is linear over the concentration range studied.