Prediction of steady-state verapamil plasma concentrations in children and adults

A program that calculates a value of clearance for an individual patient prior to reaching steady state in the early stages of aminophylline therapy is presented. The program is written for the Texas Instruments TI-59 programmable calculator and may be used with or without the PC-100C printer. The program can provide clinically useful information concerning projected plasma concentrations prior to reaching steady state with an accurate history of the dose administration and serum concentration determination. If the patient has not received xanthene therapy prior to admission, only one serum sample is required. If there has been prior drug exposure, a second serum sample is required. An iterative technique, which would be impractical to use without calculator assistance, is employed to make these determinations.

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Comparison of Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Solithromycin (CEM-101) in Healthy Adult Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00766-12 ◽

2012 ◽

Vol 56 (10) ◽

pp. 5076-5081 ◽

Cited By ~ 39

Author(s):

Keith A. Rodvold ◽

Mark H. Gotfried ◽

J. Gordon Still ◽

Kay Clark ◽

Prabhavathi Fernandes

Keyword(s):

Steady State ◽

High Performance ◽

Healthy Adult ◽

Plasma Concentrations ◽

Epithelial Lining ◽

Time Curve ◽

Epithelial Lining Fluid ◽

Once Daily ◽

Drug Concentrations ◽

The Mean

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.

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Effect of CYP2D6 and CYP2C9 genotypes on fluoxetine and norfluoxetine plasma concentrations during steady-state conditions

European Journal of Clinical Pharmacology ◽

10.1007/s00228-003-0707-y ◽

2004 ◽

Vol 59 (12) ◽

pp. 869-873 ◽

Cited By ~ 42

Author(s):

Pedro Dorado ◽

Roland Berecz ◽

Antonio P. Gonz�lez ◽

Eva M. Pe�as-LLed� ◽

Adri�n LLerena

Keyword(s):

Steady State ◽

Plasma Concentrations

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Monitoring plasma concentrations of psychotropic drugs

Drug and Therapeutics Bulletin ◽

10.1136/dtb.12.2.6 ◽

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.

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Clopidogrel

Fibrinolytic and Antithrombotic Therapy ◽

10.1093/oso/9780195155648.003.0013 ◽

2006 ◽

Author(s):

Richard C. Becker ◽

Frederick A. Spencer

Keyword(s):

Steady State ◽

Oral Dose ◽

Oral Administration ◽

Randomized Clinical Trials ◽

Peak Plasma ◽

Parent Compound ◽

Plasma Concentrations ◽

Significant Inhibition ◽

Inhibiting Effect ◽

Dependent Inhibition

Clopidogrel, a thienopyridine derivative, is a novel platelet antagonist that is several times more potent than ticlopidine but associated with fewer adverse effects. After repeated 75-mg oral doses of clopidogrel, plasma concentrations of the parent compound, which has no platelet-inhibiting effect, are very low. Clopidogrel is extensively metabolized in the liver. The main circulating metabolite is a carboxylic acid derivative with a plasma elimination half-life of 7.7 ± 2.3 hours. Approximately 50% of an oral dose is excreted in the urine and the remaining 50% in feces over the following 5 days. Dose-dependent inhibition of platelet aggregation is observed 2 hours after a single oral dose of clopidogrel, with a more significant inhibition achieved with loading doses (≥300 mg) by approximately 6 hours. Repeated doses of 75 mg of clopidogrel per day inhibit adenosine diphosphate (ADP)-mediated aggregation, with steady state being reached between day 3 and day 7. At steady state, the average inhibition to ADP is between 40% and 60%. Based on ex vivo studies, clopidogrel is approximately 100-fold more potent than ticlopidine. There are no cumulative antiplatelet effects with prolonged oral administration. The combined administration of clopidogrel (300 mg loading dose) and aspirin yields a readily discernible platelet-inhibiting effect within 90 to 120 minutes. Clopidogrel selectively inhibits the binding of ADP to its platelet receptor (P2Y12) and the subsequent G-protein–linked mobilization of intracellular calcium and activation of the glycoprotein (GP)IIb/IIIa complex (Gachet et al., 1992). The specific receptor has been cloned and is abundantly present on the platelet surface (Hollopter et al., 2001). Clopidogrel has no direct effect on cyclooxygenase, phosphodiesterase, or adenosine uptake. Clopidogrel is rapidly absorbed following oral administration with peak plasma levels of the predominant circulating metabolite occurring approximately 60 minutes later. Administration with meals does not significantly modify the bioavailability of clopidogrel. The available information suggests that clopidogrel offers safety advantages over ticlopidine, particularly with regard to bone marrow suppression and other hematologic abnormalities. Although thrombotic thrombocytopenic purpura (TTP) has been reported with clopidogrel (Bennett et al., 2000), its occurrence (11 cases per 3 million patients treated) is rare, and has not been reported in randomized clinical trials performed to date.

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8-Hydroxylation and Glucuronidation of Mirtazapine in Japanese Psychiatric Patients: Significance of the Glucuronidation Pathway of 8-Hydroxy-Mirtazapine

Pharmacopsychiatry ◽

10.1055/a-0918-6408 ◽

2019 ◽

Vol 52 (05) ◽

pp. 237-244

Author(s):

Masataka Shinozaki ◽

Jason Pierce ◽

Yuki Hayashi ◽

Takashi Watanabe ◽

Taro Sasaki ◽

...

Keyword(s):

Body Weight ◽

Steady State ◽

Plasma Levels ◽

High Performance ◽

Psychiatric Patients ◽

Plasma Concentrations ◽

Steady State Concentration ◽

Chain Reaction ◽

Polymerase Chain ◽

State Concentration

Abstract Introduction To investigate the metabolism of mirtazapine (MIR) in Japanese psychiatric patients, we determined the plasma levels of MIR, N-desmethylmirtazapine (DMIR), 8-hydroxy-mirtazapine (8-OH-MIR), mirtazapine glucuronide (MIR-G), and 8-hydroxy-mirtazapine glucuronide (8-OH-MIR-G). Methods Seventy-nine Japanese psychiatric patients were treated with MIR for 1–8 weeks to achieve a steady-state concentration. Plasma levels of MIR, DMIR, and 8-OH-MIR were determined using high-performance liquid chromatography. Plasma concentrations of MIR-G and 8-OH-MIR-G were determined by total MIR and total 8-OH-MIR (i. e., concentrations after hydrolysis) minus unconjugated MIR and unconjugated 8-OH-MIR, respectively. Polymerase chain reaction was used to determine CYP2D6 genotypes. Results Plasma levels of 8-OH-MIR were lower than those of MIR and DMIR (median 1.42 nmol/L vs. 92.71 nmol/L and 44.96 nmol/L, respectively). The plasma levels (median) of MIR-G and 8-OH-MIR-G were 75.00 nmol/L and 111.60 nmol/L, giving MIR-G/MIR and 8-OH-MIR-G/8-OH-MIR ratios of 0.92 and 59.50, respectively. Multiple regression analysis revealed that smoking was correlated with the plasma MIR concentration (dose- and body weight–corrected, p=0.040) and that age (years) was significantly correlated with the plasma DMIR concentration (dose- and body weight–corrected, p=0.018). The steady-state plasma concentrations of MIR and its metabolites were unaffected by the number of CYP2D6*5 and CYP2D6*10 alleles. Discussion The plasma concentration of 8-OH-MIR was as low as 1.42 nmol/L, whereas 8-OH-MIR-G had an approximate 59.50 times higher concentration than 8-OH-MIR, suggesting a significant role for hydroxylation of MIR and its glucuronidation in the Japanese population.

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Fasting Remnant Lipoprotein Cholesterol and Triglyceride Concentrations Are Elevated in Nondiabetic, Insulin-Resistant, Female Volunteers1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.84.11.6136 ◽

1999 ◽

Vol 84 (11) ◽

pp. 3903-3906 ◽

Cited By ~ 1

Author(s):

Fahim Abbasi ◽

Tracey McLaughlin ◽

Cindy Lamendola ◽

Helen Yeni-Komshian ◽

Akira Tanaka ◽

...

Keyword(s):

Steady State ◽

Plasma Concentrations ◽

Lipoprotein Metabolism ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Insulin Resistant ◽

Remnant Lipoprotein ◽

Increased Risk ◽

Resistant Group ◽

State Plasma

This study was initiated to test the hypothesis that plasma concentrations of remnant lipoproteins would be higher after an overnight fast in insulin-resistant compared to insulin-sensitive volunteers. Forty-three healthy nonobese women were studied, divided into insulin-resistant (n = 21) and insulin-sensitive (n = 22) groups on the basis of their steady state plasma glucose (SSPG) concentration at the end of a 180-min infusion of octreotide acetate, insulin, and glucose. Under these conditions, steady state plasma insulin concentrations are similar in all subjects (∼60μ U/mL), and the higher the SSPG concentrations, the more insulin resistant the individual. By selection, mean (±sem) SSPG concentrations were significantly higher (P < 0.001) in the insulin-resistant group (210 ± 7 vs. 78 ± 3 mg/dL). In addition, the insulin-resistant group had higher triglycerides (198 ± 27 vs. 101 ± 12 mg/dL; P < 0.005) and lower high density lipoprotein cholesterol (48 ± 4 vs. 60 ± 4 mg/dL; P < 0.05) concentrations. Finally, insulin resistance was associated with higher remnant lipoprotein particle concentrations of cholesterol (7.2 ± 0.8 vs. 4.4 ± 0.3; P < 0.005) and triglycerides (22.2 ± 3.4 vs. 8.5 ± 1.0; P < 0.001). All of these differences were seen despite the fact that the two groups were similar in terms of age and body mass index. These results identify additional abnormalities in lipoprotein metabolism that may contribute to the increased risk of coronary heart disease seen in insulin-resistant, nondiabetic subjects (syndrome X).

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