Monitoring plasma concentrations of psychotropic drugs

1974 ◽  
Vol 12 (2) ◽  
pp. 6-8
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Tissue Concentration ◽  
Plasma Concentrations ◽  
Water Concentration ◽  
Plasma Samples ◽  
Active Metabolites ◽  
The Relationship ◽  
The Brain ◽  
Reliable Methods

Techniques are now available for estimating the plasma concentration of several drugs used in psychiatry. These techniques are clearly important for research but they can hardly be expected to improve the clinical management of patients unless the estimation is sensitive, reliable and reasonably quick; the method should be specific for the particular drug but should also specifically estimate any active metabolites. Even when reliable figures have been obtained, much more information is needed before they can be interpreted. The relationship between plasma (or plasma water) concentration and relevant tissue concentration (e. g. in the brain) must be known. Plasma samples should be taken at appropriate times, e. g. after the attainment of ‘steady-state’ conditions: plasma and tissue levels will then be in equilibrium. Diagnoses must be soundly based if inferences are to be drawn. Reliable methods of assessing clinical response must be available. These requirements pose difficult problems in psychiatry.

scholarly journals The Role of Pharmacokinetics in Anaesthesia: Application to Intravenous Infusions

1987 ◽  
Vol 15 (1) ◽  
pp. 7-14 ◽  
Author(s):  
D. R. Stanski
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Drug Dose ◽  
Metabolic Clearance ◽  
Drug Infusion ◽  
Fixed Rate ◽  
Elimination Half

Pharmacokinetic concepts describe the relationship between drug dose and resulting plasma concentration. A drug's pharmacokinetic profile can be described by distribution and elimination half-lives, initial volume of distribution, steady-state distribution volume, and metabolic and distributional clearance. After initiating a fixed rate of drug infusion, four to five terminal elimination half-lives are required to reach a steady state of constant plasma concentration. If a loading dose is given, a steady state can be achieved more rapidly. The most rapid method of achieving a constant plasma concentration involves using a variable rate of drug infusion that adjusts for the metabolic clearance and distribution of the drug. Computer-driven infusion pumps can be used to rapidly achieve, then maintain, constant plasma concentrations of a drug.

CYP2D6 genotypes in association with steady state plasma concentrations of active metabolites of tamoxifen in patients with breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 634-634 ◽  
Author(s):  
H. Lim ◽  
H. Lee ◽  
K. Lee ◽  
E. Lee ◽  
I. Jang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Steady State ◽  
Plasma Concentrations ◽  
Cancer Center ◽  
Cyp2d6 Genotype ◽  
Active Metabolites ◽  
Fluorescence Detector ◽  
Wilcoxon Rank Sum Test ◽  
Center Hospital ◽  
State Plasma

634 Background: Tamoxifen is a prodrug that is metabolized to active metabolites, Z-4-hydroxy-N-desmethyltamoxifen (BX) and Z-4-hydroxy-tamoxifen (4OH) where CYP2D6 plays a major role in the conversion. Genetic polymorphisms of CYP2D6 by ethnicities are well known with CYP2D6*10 in Asians (up to 50% in Koreans), and CYP2D6 *2 and *4 in American Whites as major variant alleles. We analyzed the steady state plasma concentrations of tamoxifen and its metabolites in patients (pts) with breast cancer to evaluate their associations with various CYP2D6 genotypes. Methods: Blood samples were collected from 219 pts on tamoxifen, 20 mg daily as adjuvant therapy for more than 3 months at National Cancer Center, Korea. Plasma tamoxifen, N-desmethyltamoxifen, BX, 4OH were measured by validated HPLC with fluorescence detector, and analyzed according to CYP2D6 genotype groups by Wilcoxon rank sum test. CYP2D6*10, CYP2D6*5 and CYP2D6*2×2 were identified by PCR-RFLP methods, and the rests were classified as CYP2D6*1 (wild type). This study was approved by IRB at National Cancer Center Hospital (NCCNHS04–033) and conducted after informed consent obtained by the patients. Results: Thus far, we measured plasma concentration of tamoxifen and its metabolites for 158 pts among 198 pts genotyped. 59 pts (29.8%) carried CYP2D6*1/*1, 84 pts (42.4%) *1/*10 and 49 pts (24.7%) *10/*10. Other types were CYP2D6*1/*5 (8.6%), *5/*5 (1.0%), *1/*2×2 (2.5%). Pts with CYP2D6 *10/*10 (n=40) demonstrated significantly lower steady state plasma concentrations of BX and 4OH than those with other genotypes (n=118) (BX: 7.9 vs.19.2. ng/ml [95 % CI; 5.5–10.4 vs. 15.8–22.7 ng/ml] p<0.0001; 4OH: 1.5 vs. 2.8 ng/ml [95 % CI; 1.1–2.0 vs. 2.3–3.3 ng/ml] p<0.0001), whereas there were no differences with *1/*10 (n=64) vs. without *10 allele (n=54) (BX: 20.6 vs. 18.1 ng/ml; 4OH: 2.9 vs. 2.7 ng/ml). Basically no significant differences in BX/4OH or other compounds by various CYP2D6*2 ×2 and *5 alleles were observed. Conclusions: The steady state plasma concentrations of BX and 4OH were significantly low with CYP2D6 *10/*10 genotype, and their clinical implications need to be explored.(Supported by a grant NCC-0410590). No significant financial relationships to disclose.

scholarly journals Risk Factors for a Low Linezolid Trough Plasma Concentration in Acute Infections

2013 ◽  
Vol 57 (4) ◽  
pp. 1913-1917 ◽  
Author(s):  
Laura Morata ◽  
Marta Cuesta ◽  
Jhon F. Rojas ◽  
Sebastian Rodriguez ◽  
Merce Brunet ◽  
...  
Keyword(s):  
Risk Factors ◽  
Steady State ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Time Curve ◽  
Content Type ◽  
Acute Infections ◽  
Trough Plasma Concentration ◽  
Dependent Activity ◽  
Trough Plasma

ABSTRACTLinezolid is an antibiotic with time-dependent activity, and both the percentage of time that plasma concentrations exceed the MIC and the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC24/MIC ratio) are associated with clinical response. The aim of this study was to analyze the linezolid trough plasma concentration (Cmin) and to determine factors associated with aCmin< 2 mg/liter and other clinically relevant thresholds. Characteristics of 78 patients receiving 600 mg/12 h of linezolid with aCmindetermination at the steady state and within the first 10 days of treatment were retrospectively reviewed. Concentrations were measured using high-pressure liquid chromatography. Univariate and multivariate analysis were performed to identify risk factors of lowCmin. A total of 29.5% of patients had aCmin< 2 mg/liter. The percentage was significantly higher in patients with an estimated glomerular filtration (eGF) > 80 ml/min, in intensive care unit (ICU) patients, and in patients with an infection due toStaphylococcus aureus. The independent predictors ofCmin< 2 mg/liter were an eGF > 80 ml/min (odds ratio [OR], 10; 95% confidence interval [CI], 2.732 to 37.037;P= 0.001) and infection due toS. aureus(OR, 5.906; 95% CI, 1.651 to 21.126;P= 0.006). A linezolidCminof <2 mg/liter was found in 29.5% of cases, and the risk was significantly higher among those with an eGF > 80 ml/min and in infections due toS. aureus. In patients with severe sepsis, a loading dose or continuous infusion and drug monitoring could improve the pharmacodynamic parameters associated with linezolid efficacy.

scholarly journals PH metric method for the determination of nicotinic acid in plasma

1977 ◽  
Vol 5 (4) ◽  
pp. 390-392
Author(s):  
J Gravesen
Keyword(s):  
Single Dose ◽  
Steady State ◽  
Standard Deviation ◽  
Plasma Concentration ◽  
Sustained Release ◽  
Nicotinic Acid ◽  
Plasma Samples ◽  
Slope Ratio ◽  
Male Patients

The acidimetric method for the determination of nicotinic acid (NA) using Lactobacillus plantarum ATCC 8014 (Lactobacillus arabinosus 17-5) has been simplified and thus made less time consuming, and the sensitivity has been increased fivefold by replacement of the titration by a pH determination. As the regression of the decrease in pH on the amount of NA was found linear within a range of 1 to 4 ng of NA per ml, the calculations were performed according to the slope-ratio principle. The NA concentration of plasma was determined with a coefficient of variation of 5 to 7%, which rose to about 10% at low NA concentrations. Assays of fasting plasma samples from 13 hyperlipidemic male patients showed a group mean NA concentration of 80 +/- 55 ng/ml (mean +/- 2 standard deviation), before treatment, and 705 +/- 544 ng/ml (mean +/- 2 standard deviation) during therapy with sustained release NA preparations, of which a single dose, ingested during steady-state conditions, doubled or tripled the plasma concentration within 1 to 3 h.

scholarly journals Variation in Plasma Concentration of Insulin-like Growth Factor-l and its Covariation with Liveweight in Mice

1987 ◽  
Vol 40 (3) ◽  
pp. 287 ◽  
Author(s):  
H T Blair ◽  
SN McCutcheon ◽  
DDS Mackenzie ◽  
PD Gluckman ◽  
JE Ormsby
Keyword(s):  
Genetic Variation ◽  
Plasma Concentration ◽  
Growth Factor ◽  
Litter Size ◽  
Genetic Factors ◽  
Plasma Concentrations ◽  
Early Age ◽  
Selection Experiment ◽  
Insulin Like Growth Factor ◽  
The Relationship

Three experiments were undertaken to examine the degree and causes of variation in plasma concentrations of insulin-like growth factor-l (IOF-I) in mice. The relationship between IOF-l concentrations and liveweight was also examined. In all three experiments, a number of non-genetic factors were found to contribute significantly to the variation in IOF-l concentrations, the most important of these being sex and litter size. In one experiment, where pups from 16 litters were cross-fostered to avoid the confounding of maternal and direct genetic effects, a heritability of 0'40 � 0�27 was estimated for plasma IOF-l concentration at 35 days of age. To examine further the existence of genetic variation in plasma concentrations of IOF-l and the genetic covariation between plasma IOF-l levels and other body traits, a selection experiment with mice has been initiated. Moderate to strong phenotypic correlations between IOF-l concentrations and weight at an early age have been found in all three experiments.

Drug entry into and distribution within brain and cerebrospinal fluid: [14C]urea pharmacokinetics

1982 ◽  
Vol 242 (3) ◽  
pp. R339-R348 ◽  
Author(s):  
S. I. Rapoport ◽  
R. Fitzhugh ◽  
K. D. Pettigrew ◽  
U. Sundaram ◽  
K. Ohno
Keyword(s):  
Cerebrospinal Fluid ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Nonlinear Least Squares ◽  
Compartment Model ◽  
Plasma Distribution ◽  
Urea Uptake ◽  
Cerebral Capillary ◽  
The Brain ◽  
Brain Extracellular Space

A four-compartment model was derived to analyze drug exchange among cerebral capillary plasma, cerebrospinal fluid (CSF), and the brain extracellular and intracellular (or bound) compartments. Equations that were derived incorporated the factor of cerebral blood flow. They were fit by nonlinear least squares to measured brain, plasma, and CSF (when available) concentrations of [14C]urea in the rat, in response to a step increase in plasma concentration, to intravenous infusion, or to a bolus injection of tracer. Best-fit values for the transfer constants were consistent among the three administrative regimens and agreed with published values, when available. Expressions also were derived and numerically evaluated for the lower limit of the brain extracellular space, for half times of brain [14C]urea uptake, and for the steady-state brain/plasma distribution volume. The model should make it possible to use transfer constants obtained for a given drug from one study (e.g., constant plasma concentration) to predict brain concentrations from measured plasma concentrations in other acute or chronic studies.

Increased plasma concentrations of the 5-HT precursor amino acid tryptophan and other large neutral amino acids in violent criminals

1997 ◽  
Vol 27 (2) ◽  
pp. 477-481 ◽  
Author(s):  
T. ERIKSSON ◽  
L. LIDBERG
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Plasma Concentrations ◽  
Healthy Controls ◽  
Violent Behaviour ◽  
Violent Crimes ◽  
Amino Acid Tryptophan ◽  
The Relationship ◽  
The Brain ◽  
Abnormal Brain

Background. Aggression has been suggested to be related to abnormal brain 5-HT activity. This amine is synthesized in brain from tryptophan, which is transported through the blood–brain barrier in competition with other amino acids. The relationship between tryptophan and its endogenous amino acid competitors in plasma might thus influence the availability of tryptophan in the brain and consequently brain 5-HT activity.Methods. Plasma amino acids were determined in 89 offenders who had committed various violent and non-violent crimes and in 14 healthy controls.Results. Both tryptophan and its competitors were higher in offenders who had committed violent crimes compared both with non-violent offenders and with controls. No difference was, however, seen in the relationship between tryptophan and its competitors.Conclusions. The results support the contention that violent behaviour is related to biochemical deviations but could not explain a possible decreased brain 5-HT activity.

scholarly journals Association Between Genetic Polymorphisms and Steady-State Plasma Concentration of Warfarin Optical Isomers

2020 ◽  
Author(s):  
Yiwei Liu ◽  
Quanyao Chen ◽  
Wai-Kit Ming ◽  
Feiyu Wang ◽  
Rongfang Lin ◽  
...  
Keyword(s):  
Steady State ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Ultra Performance Liquid Chromatography ◽  
Optical Isomers ◽  
Chi Square ◽  
Genotype Frequencies ◽  
Significant Difference ◽  
Chi Square Analysis ◽  
State Plasma

Abstract Background We evaluated the effects of CYP2C19*2, CYP2C9*3, VKORC1 A1639G, CYP4F2, and MDR1 C3435T gene polymorphisms on the plasma concentrations of R- and S-warfarin enantiomers at the same dose.Methods The plasma concentrations of R- and S-warfarin were determined by ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) in 136 patients. The PCR-RFLP genotyping results were verified by pyrosequencing. The Hardy–Weinberg equilibrium of genotype frequencies was assessed using the Chi-square analysis. Relationships between genotype and plasma concentrations of the enantiomers were analyzed by Kruskal–Wallis test.Results There was no significant difference in the dosage between groups (P > 0.05). The CYP2C19*2, CYP2C9*3, CYP4F2, MDR1 C3435T, and VKORC1 A1639G mutation frequencies were 37.5%, 6.25%, 19.12%, 31.25%, and 3.31%, respectively. The plasma concentrations were non-normally distributed. The S-warfarin plasma concentration was significantly higher in CYP2C9*3 carriers than in non-carriers (P = 0.018) and in patients carrying the T allele of CYP4F2 than those carrying the C allele (P = 0.03). The VKORC1 A1639G polymorphism did not affect the steady-state plasma concentrations of R- and S-warfarin. The enantiomer ratio in homozygous patients (GG) was significantly lower than that in heterozygous patients (GA) and those lacking the mutation (AA) (P = 0.039). Enantiomer plasma levels were not significantly different between MDR1 C3435T and CYP2C19*2 (P > 0.052).Conclusions The CYP2C9*3 and CYP4F2 mutations are associated with increased plasma concentrations of S-warfarin. The VKORC1 A1639G polymorphism might affect the plasma ratio of R- and S-warfarin. Maintenance dose reduction during warfarin administration can be considered for patients with the CYP2C9*3 and CYP4F2 mutations.

Dextromethorphan phenotyping as a test for prediction of tamoxifen (TAM) activation in breast cancer patients receiving adjuvant hormone therapy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e13019-e13019
Author(s):  
Milena Gusella ◽  
Laura Bertolaso ◽  
Felice Pasini ◽  
Yasmina Modena ◽  
Antonio Bononi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Steady State ◽  
Cancer Patients ◽  
Plasma Levels ◽  
Linear Regression Analysis ◽  
Plasma Concentrations ◽  
Breast Cancer Patients ◽  
Active Metabolites ◽  
Adjuvant Hormone Therapy ◽  
State Plasma

e13019 Background: TAM is mainly metabolized by CYP2D6 to form its most active metabolites, 4hydroxy-tamoxifen (4OH-T) and endoxifen (END). Because of its long half-life, steady state is reached after around 4 months of continuous intake. The wide variable inter-patient activity of CYP2D6 might influence drug efficacy. A multi-institutional study in north Italy is evaluating the relationship between END levels and outcome. As a part of it, we investigated the role of dextromethorphan (DM), a probe drug for CYP2D6 enzymatic activity, as a potential phenotyping test for TAM activation. Methods: Twenty-nine breast cancer patients (75% postmenopausal) on adjuvant TAM therapy (20 mg/die) were investigated. They received a single dose (15 mg) of oral DM before starting TAM and their urines were collected over the10 following hours. Simultaneous quantitative determination of DM and its metabolite dextrorphan (DO) was performed in urines to estimate their log transformed metabolic ratio (LMR=logDM/DO). After 4 months a blood sample was collected to characterize TAM exposure at steady state; plasma levels of TAM, END, 4OH-T and the non active END precursor N-desmethyltamoxifen (NDT) were quantified by HPLC. Linear regression analysis and t test were performed for correlating LMR and drug plasma levels. Results: LMR varied between -2.15 and 0.90 (median: -1.37) while steady state plasma levels of END varied between 1.9 and 15.0 ng/ml (median: 4.36) and 4OH-T between 0.9 to 3.1 ng/ml (median:1.72). A significant correlation (r = 0.56; p= 0.0013) was found between LMR and END plasma concentrations. The patients with high LMR (> median value), compared to patients with low LMR, had lower END (3.7 vs 7.5 ng/ml, p=0.0003), lower 4OH-T (1.6 vs 2.1 ng/ml, p=0.04) and, accordingly, higher NDT (291.2 vs 198.2 ng/ml, p=0.025). Conclusions: DM/DO urine ratio obtained before starting therapy correlates with TAM biotransformation activity and can predict steady state active metabolites exposure in individual patients. This phenotyping test is fast, simple and unexpensive and could contribute to the personalization of adjuvant breast cancer treatment. Funded by Regione Veneto.

scholarly journals Pharmacokinetics and Intestinal Metabolism of Compound K in Rats and Mice

Pharmaceutics ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 129 ◽  
Author(s):  
Ji-Hyeon Jeon ◽  
Bitna Kang ◽  
Sowon Lee ◽  
Sojeong Jin ◽  
Min-Koo Choi ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Plasma Samples ◽  
Relative Quantification ◽  
Intestinal Metabolism ◽  
Compound K ◽  
Common Features ◽  
Fecal Recovery ◽  
Rats And Mice ◽  
Rat Bile

We aimed to investigate the plasma concentration, tissue distribution, and elimination of compound K following the intravenous administration of compound K (2 mg/kg) in rats and mice. The plasma concentrations of compound K in mice were much higher (about five-fold) than those in rats. In both rats and mice, compound K was mainly distributed in the liver and underwent biliary excretion. There was 28.4% fecal recovery of compound K in mice and 13.8% in rats, whereas its renal recovery was less than 0.1% in both rats and mice. Relative quantification of compound K and its metabolite protopanaxadiol (PPD) in rat bile and intestinal feces indicated that the metabolism from compound K into PPD occurred in the intestine but not in the plasma. Therefore, PPD detected in the plasma samples could have been absorbed from the intestine after metabolism in control rats, while PPD could not be detected in the plasma samples from bile duct cannulated rats. In conclusion, mice and rats shared common features such as exclusive liver distribution, major excretion pathway via biliary route, and intestinal metabolism to PPD. However, there were significant differences between rats and mice in the plasma concentrations of compound K and the fecal recovery of compound K and PPD.

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