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William J Jusko

Publications and source records attributed to William J Jusko.

At least 37 records · Page 2Linked to original sources
PubMed2005

Comparison of dexamethasone pharmacokinetics in female rats after intravenous and intramuscular administration.

This study seeks a route of drug administration that would produce a pharmacokinetic profile for dexamethasone not significantly different from the intravenous route in female rats and would offer reproducible drug input with minimal stress to the animals. The intramuscular (i.m.) route of drug administration vs intravenous (i.v.) injection were compared in three female Wistar rats administered 1 mg/kg dexamethasone phosphate. Dexamethasone plasma concentrations were measured by a normal phase HPLC assay for 12 h after drug administration. Dexamethasone exhibited monoexponential behavior after intravenous dosing and was absorbed rapidly after intramuscular dosing (absorption half-life of 14 min) with 86% bioavailability. Dexamethasone had a terminal half-life of 2.3 h after drug administration by either route. The volume of distribution of 0.78 l/kg and the clearance of 0.23 l/h/kg are in good agreement with reported pharmacokinetic parameters in male rats. Intravenous dosing can be replaced by intramuscular dosing without causing any marked difference in dexamethasone pharmacokinetics.

Adrenal Cortex Hormones↗
PubMed2005

Pharmacodynamic interactions between recombinant mouse interleukin-10 and prednisolone using a mouse endotoxemia model.

The pharmacodynamic interactions between recombinant mouse interleukin-10 (IL-10) and prednisolone were examined in lipopolysaccharide (LPS)-induced experimental endotoxemia in Balb/c mice. Treatment phases consists of single doses of IL-10 (10 microg/kg i.p.), prednisolone (25 (mg/kg i.p.), IL-10 (2.5 microg/kg i.p.) with prednisolone (6.25 mg/kg i.p.), or placebo (saline). Measurements included plasma steroid kinetics and IL-10 concentrations and responses to LPS including proinflammatory cytokines (TNF-alpha, IFN-gamma) and circulatory NO measured as plasma nitrate/nitrite concentrations. The intraperitoneal dosing of LPS produced large and transient elevations of plasma TNF-alpha, IFN-gamma, and NO concentrations. Noncompartmental and model fitting using extended indirect response models based on drug inhibition of multiphase stimulation of biomarkers by LPS were used to describe the in vivo pharmacodynamics and drug interactions. Dosing with prednisolone, IL-10, or their combinations produced strong inhibition of cytokine and NO production. The IC50 values of prednisolone ranged from 54 to 171 ng/mL, and IC50 values for IL-10 ranged from 0.06 to 0.69 ng/mL. The production of NO was described as a cascading consequence of the TNF-alpha and IFN-gamma plasma concentrations. The joint dosing of IL-10 with prednisolone produces moderately synergistic immunosuppressive effects in this system. Both drugs were sufficiently protective in suppressing the inflammatory mediators when administered prior to the LPS trigger, while such effects were modest when administered after the inflammatory stimulus was provoked. The integrated and complex pharmacokinetic/pharmacodynamic models well capture the in vivo processes, drug potencies, and interactions of IL-10 and prednisolone.

Animals↗
PubMed2005

Population cell life span models for effects of drugs following indirect mechanisms of action.

Pharmacokinetic/pharmacodynamic (PK/PD) models for hematological drug effects exist that assume that cells are produced by a zero- or first-order process, survive for a specific duration (cell lifespan), and then are lost. Due to the fact that delay differential equations (DDE) are needed for cell lifespan models, their software implementation is not straightforward. Our objective is to demonstrate methods to implement three different cell lifespan models for dealing with hematological drug effects and to evaluate the performance of NONMEM to estimate the model parameters. For the basic lifespan indirect response (LIDR) model, cells are produced by a zero-order process and removed due to senescence. The modified LIDR model adds a precursor pool. The LIDR model of cytotoxicity assumes a three-pool indirect model to account for the cell proliferation with capacity-limited cytotoxicity followed by maturation, and removal from the circulation. A numerical method (method of steps) implementing DDE in NONMEM was introduced. Simulation followed by estimation was used to evaluate NONMEM performance and the impact of the minimization algorithm (first-order method vs. first-order conditional estimation method) and the model for residual variability on the estimates of the population parameters. The FOCE method combined with log-transformation of data was found to be superior. This report provides methodology that will assist in application of population methods for assessing hematological responses to various types of drugs.

Algorithms↗
PubMed2005

Pharmacokinetics and pharmacodynamics of PEGylated IFN-beta 1a following subcutaneous administration in monkeys.

PURPOSE: To characterize the pharmacokinetic/pharmacodynamic (PK/PD) properties of a new polyethylene glycol (PEG) conjugate formulation of interferon (IFN)-beta la following subcutaneous (SC) administration in monkeys. METHODS: Single SC injections of 0.3, 1, and 3 million international units (MIU)/kg of PEG-IFN-beta 1a were administered to 3 groups of cynomolgus monkeys (n = 4 each). Plasma concentrations of drug and neopterin, a classic biomarker for IFN-beta PD, were measured at various time-points after dosing. PK/PD profiles were described by noncompartmental methods and pooled data by an integrated mathematical model, where fixed and delayed concentration-time profiles were used as driving functions in an indirect stimulatory response model. RESULTS: PEG-IFN-beta 1a was rapidly absorbed, with peak concentrations observed at about 4-5 h. Compared to previous identical SC doses of IFN-beta la, administration of 1 and 3 MIU/kg of pegylated drug resulted in 27- and 16-fold increases in area under the concentration-time curves. Neopterin concentrations followed a typical dose-dependent biphasic pattern. Pooled PD profiles were well-described by the PK/PD model, and the neopterin elimination rate (0.0190 h(-1)) is consistent with previous estimates. CONCLUSIONS: The PEG-modification of IFN-beta la provides enhanced drug exposure and similar pharmacodynamics of neopterin compared to the unmodified formulation.

2',5'-Oligoadenylate Synthetase↗
PubMed2005

Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after multiple subcutaneous doses in healthy subjects.

A pharmacokinetic and pharmacodynamic (PK/PD) model for recombinant human erythropoietin (Epoetin alfa) in healthy subjects was developed to describe the time profiles of changes in serum Epoetin alfa and the pharmacological responses of percent reticulocytes, total red blood cell counts, and hemoglobin after single and multiple subcutaneous administration of Epoetin alfa. Data used in the development of the model were obtained from a clinical study carried out in healthy volunteers in which Epoetin alfa was administered either as 150 IU/kg three-times-a-week (t.i.w.) or fixed 40,000 IU weekly (q.w.) doses for 4 weeks. A dual-absorption rate model (fast zero-order and slow first-order inputs) with linear disposition kinetics was used to characterize the pharmacokinetics of erythropoietin after subcutaneous administration. A new catenary cell production and lifespan loss model was used to fit the pharmacodynamic data yielding estimates of SC50, Smax, and other pharmacodynamic parameters. Flip-flop kinetics was apparent in the pharmacokinetics as the absorption rate was slower (k(a) = 0.7 day(-1)) than the elimination rate (CL/V(d) = 1.2-9.2 day(-1)). In the pharmacodynamics, an SC50 of 58 mIU/mL was estimated indicating that low serum erythropoietin concentrations were sufficient to produce pharmacological effects. The established PK/PD model predicts similar pharmacological responses of hemoglobin and total red blood cell counts for the 150 IU/kg t.i.w. and 40,000 IU q.w. regimens in healthy subjects.

Adolescent↗
PubMed2005

Semi-mechanistic pharmacokinetic/pharmacodynamic modelling of the antimalarial effect of artemisinin.

PURPOSE: To characterize artemisinin pharmacokinetics (PK) and its antimalarial activity in vivo. METHODS: Artemisinin salivary concentration and parasite count data were obtained from Vietnamese malaria patients receiving two different dosage regimens. PK data were analysed using a previously developed semiphysiological model incorporating autoinduction of eliminating enzymes. A pharmacodynamic (PD) model reflecting different stages of the parasite life-cycle was developed and fitted to the data. The model included visible and invisible compartments as well as sensitive, insensitive, and injured parasite stages. Salivary artemisinin concentrations functioned as the driving force for the observed decrease in the number of parasites. RESULTS: Large interindividual variability was observed in both PK and PD data. The PK model described reasonably well the observed decrease in salivary concentrations after repeated drug administration. The preinduction hepatic extraction ratio of artemisinin was estimated to be 0.87 with a volume of distribution of 27 L. Artemisinin half-life averaged 0.7 h. Incorporation of a saturable hepatic elimination affecting the first-pass extraction as well as a higher intrinsic clearance in female patients resulted in the best fit of the model to the data. The PD model described the decrease in the number of parasites during the course of treatment well. The longest mean transit time of parasites from sensitive, visible to invisible to insensitive visible stages was found to be 34.5 h through one life-cycle. The half-life of injured parasites was 2.7 h. CONCLUSIONS: The proposed semimechanistic PK/PD model successfully described the time course of both salivary artemisinin concentrations after repeated dosing and the number of parasites in patients treated with the drug.

Antimalarials↗
PubMed2005

Temporal profiling of the transcriptional basis for the development of corticosteroid-induced insulin resistance in rat muscle.

Elevated systemic levels of glucocorticoids are causally related to peripheral insulin resistance. The pharmacological use of synthetic glucocorticoids (corticosteroids) often results in insulin resistance/type II diabetes. Skeletal muscle is responsible for close to 80% of the insulin-induced systemic disposal of glucose and is a major target for glucocorticoid-induced insulin resistance. We used Affymetrix gene chips to profile the dynamic changes in mRNA expression in rat skeletal muscle in response to a single bolus dose of the synthetic glucocorticoid methyl-prednisolone. Temporal expression profiles (analyzed on individual chips) were obtained from tissues of 48 drug-treated animals encompassing 16 time points over 72 h following drug administration along with four vehicle-treated controls. Data mining identified 653 regulated probe sets out of 8799 present on the chip. Of these 653 probe sets we identified 29, which represented 22 gene transcripts, that were associated with the development of insulin resistance. These 29 probe sets were regulated in three fundamental temporal patterns. 16 probe sets coding for 12 different genes had a profile of enhanced expression. 10 probe sets coding for eight different genes showed decreased expression and three probe sets coding for two genes showed biphasic temporal signatures. These transcripts were grouped into four general functional categories: signal transduction, transcription regulation, carbohydrate/fat metabolism, and regulation of blood flow to the muscle. The results demonstrate the polygenic nature of transcriptional changes associated with insulin resistance that can provide a temporal scaffolding for translational and post-translational data as they become available.

Animals↗
PubMed2004

Receptor/gene-mediated pharmacodynamic effects of methylprednisolone on phosphoenolpyruvate carboxykinase regulation in rat liver.

Phosphoenolpyruvate carboxykinase (PEPCK) is the rate-limiting enzyme for gluconeogenesis. To investigate underlying mechanisms of corticosteroid (CS) action in regulating glucose, temporal patterns of hepatic PEPCK gene expression, enzyme activity, and cAMP content were examined in adrenalectomized rats receiving acute and chronic methylprednisolone (MPL) treatments. After single MPL intravenous doses, PEPCK mRNA showed a fast increase, reaching a maximum at around 0.75 h, which was followed by an immediate decline to below baseline after 4 h, an apparent acute tolerance/rebound phenomenon. However, PEPCK enzyme showed continuous hyperactivity for over 72 h. This may be the result of generation of cAMP, an important inducer of PEPCK activity, which peaked at around 6 h. During 7-day subcutaneous infusion of MPL, PEPCK mRNA showed profiles consistent with single-dose results, whereas PEPCK activity increased to a comparable maximum followed by a slow decline. However, the extent of cAMP induction was markedly higher during infusion, which could be attributed to amplification of cAMP synthesis and/or a stabilizing effect of MPL on cAMP degradation. A pharmacokinetic/pharmacodynamic model was developed based on receptor/gene mechanisms of CS action. It successfully described the dual effects of MPL on regulating PEPCK message and the post-transcriptional control by cAMP. Our results exemplify the importance of the extent and duration of steroid exposure in mediating pharmacological effects. The model provides quantitation of multiple controlling factors regulating PEPCK and presents insights into its function in glucose metabolism.

Animals↗
PubMed2004

The PEPR GeneChip data warehouse, and implementation of a dynamic time series query tool (SGQT) with graphical interface.

Publicly accessible DNA databases (genome browsers) are rapidly accelerating post-genomic research (see http://www.genome.ucsc.edu/), with integrated genomic DNA, gene structure, EST/ splicing and cross-species ortholog data. DNA databases have relatively low dimensionality; the genome is a linear code that anchors all associated data. In contrast, RNA expression and protein databases need to be able to handle very high dimensional data, with time, tissue, cell type and genes, as interrelated variables. The high dimensionality of microarray expression profile data, and the lack of a standard experimental platform have complicated the development of web-accessible databases and analytical tools. We have designed and implemented a public resource of expression profile data containing 1024 human, mouse and rat Affymetrix GeneChip expression profiles, generated in the same laboratory, and subject to the same quality and procedural controls (Public Expression Profiling Resource; PEPR). Our Oracle-based PEPR data warehouse includes a novel time series query analysis tool (SGQT), enabling dynamic generation of graphs and spreadsheets showing the action of any transcript of interest over time. In this report, we demonstrate the utility of this tool using a 27 time point, in vivo muscle regeneration series. This data warehouse and associated analysis tools provides access to multidimensional microarray data through web-based interfaces, both for download of all types of raw data for independent analysis, and also for straightforward gene-based queries. Planned implementations of PEPR will include web-based remote entry of projects adhering to quality control and standard operating procedure (QC/SOP) criteria, and automated output of alternative probe set algorithms for each project (see http://microarray.cnmcresearch.org/pgadatatable.asp).

Algorithms↗
PubMed2004

Stabilization and HPLC analysis of betamethasone sodium phosphate in plasma.

The analysis of corticosteroid prodrugs in pharmacokinetic (PK) studies poses the risk of overestimation of corticosteroid concentrations due to in vitro hydrolysis of prodrugs after sample collection. This study tests the effectiveness of enzyme inhibitors as stabilizers for betamethasone sodium phosphate (BSP) in pregnant sheep plasma samples collected during PK studies with betamethasone (BET) and provides simultaneous high-performance liquid chromatography analysis of BSP and BET. A rapid, sensitive, and specific ion-paired reversed-phase high-performance liquid chromatography assay for simultaneous measurement of BET and BSP in plasma was developed. This assay was used for analyzing samples from an in vitro prodrug hydrolysis study. Enzyme inhibitors tested were sodium arsenate (Na(2)HAsO(4)) and ethylenediaminetetraacetic acid. The BSP was administered intramuscularly to three pregnant sheep to assess in vivo PK. Samples were split with part treated with Na(2)HAsO(4) and part left natural. In vitro hydrolysis of BSP in plasma to BET could be completely inhibited by Na(2)HAsO(4), but not by ethylenediaminetetraacetic acid. The PK study showed lower concentrations of BET in samples with Na(2)HAsO(4) compared with natural samples. This study demonstrates that artifacts in PK profiles of corticosteroids due to in vitro prodrug hydrolysis can be prevented by sample treatment with enzyme inhibitors.

Animals↗
PubMed2004

Assessment of drug interactions relevant to pharmacodynamic indirect response models.

The assessment of drug interactions for a simple turnover system when the basic pharmacodynamic response is governed by indirect mechanisms was explored. This report describes a diverse array of possible in vivo pharmacodynamic effects from a combination of two drugs acting by similar or different indirect mechanisms. Various conditions of pharmacodynamic drug combinations were explored mathematically and by simulation: (a) interactions of two drugs acting simultaneously either on the production (k(in)) or on the dissipation (k(out)) processes controlling the in vivo response by competitive (four cases) or non-competitive interaction (six cases); and (b) combinations of two drugs acting on separate k(in) and k(out) processes simultaneously (four cases). A range of different combinations of drug doses was used. Plasma concentration time profiles were generated according to monoexponential disposition. Pharmacodynamic response profiles were simulated using the above conditions and characterized by descriptors such as Area Between Effect (and Baseline) Curve (ABEC) values. The interaction of agents by competitive mechanisms produced net responses that were additive in nature. Response profiles for non-competitive interactions on the same process were both antagonistic (for two drugs with effects that oppose each other) and synergistic (for two drugs that produce the same response). On the other hand, response signatures for agents acting non-competitively on the production and dissipation factors by opposing mechanisms (e.g. inhibiting k(in) plus stimulating k(out)) showed dramatic changes in net effects and produced apparent drug synergy. Net indirect response profiles for joint use of two or more drugs measured by ABEC values may look "additive", "antagonistic", or "synergistic" depending on doses, their intrinsic potencies, the nature of interaction (competitive or non-competitive) as well as their mechanisms of action. These models may help explain changes in pharmacologic responses to two agents in a more rational and mechanistic fashion than older empirical methods.

Computer Simulation↗
PubMed2004

Area/moment and compartmental modeling of pharmacokinetics during pregnancy: applications to maternal/fetal exposures to corticosteroids in sheep and rats.

PURPOSE: The pharmacokinetics of corticosteroids in pregnancy were analyzed to assess maternal/fetal disposition and factors controlling fetal exposure. Area/Moment equations and compartmental models for estimating pharmacokinetic parameters from single dose data during pregnancy were developed. METHODS: Betamethasone in the maternal/fetal circulations of sheep was measured by HPLC after maternal intramuscular injection (n = 4) of 170 microg kg(-1) of a depot formulation. Additional data for beta-methasone in sheep and dexamethasone pharmacokinetics in rats were obtained from the literature. Area/Moment equations were derived using mass balance concepts, statistical moments, and Laplace theory. Area/Moment analysis, compartmental modeling, and allometric scaling to man for betamethasone were performed using WinNonlin and ADAPT II programs. RESULTS: Polyexponential maternal/fetal profiles for corticosteroids were observed. Clearance terms for corticosteroid transfer from fetus to mother were 4-fold higher than the clearance term for transfer in the opposite direction. A placental efflux process may restrict fetal access of corticosteroids which are known PGP substrates. The elimination clearance estimates indicate that fetal metabolism plays a minor role in corticosteroid elimination. CONCLUSIONS: Generalized and specific models for maternal/fetal pharmacokinetics were developed. An efflux transport mechanism, such as the known placental expression of PGP, could explain the limited fetal exposure of corticosteroids.

Animals↗
PubMed2004

Modeling the metabolic effects of terbutaline in beta2-adrenergic receptor diplotypes.

OBJECTIVE: Our objective was to determine whether beta(2)-adrenergic receptor polymorphisms influence terbutaline-stimulated changes in glucose, insulin, and potassium concentrations in healthy adults. METHODS: Seven healthy adults homozygous for the Arg-19/Gly16/Glu27 haplotype (RGE) and seven homozygous for the Cys-19/Arg16/Gln27 haplotype (CRQ) volunteered to receive a 1-hour infusion of terbutaline (0.01 mg/kg). A 2-compartment pharmacokinetic model was fitted to the terbutaline concentrations. Concentrations of glucose and insulin were fitted simultaneously by use of a coupled feedback indirect response model. An indirect response model was also fitted to the plasma potassium concentration versus time data. The -2 log-likelihood ratio test was used to determine whether estimates of the covariates of diplotype and sex improved the model fittings. RESULTS: Demographic variables, anthropometric characteristics, and pharmacokinetics did not differ by diplotype. The coupled feedback model fitted the glucose and insulin concentration data well with excellent precision. Terbutaline stimulated production of glucose (S(1)) to a greater extent in RGE compared with CRQ diplotypes, as follows: S(1) = 0.039 +/- 0.007 (mean +/- SD) versus 0.0276 +/- 0.01, respectively (P <.05, -2 log-likelihood criterion). The baseline values, disposition rate constants for glucose (k(out1)) and insulin (k(out2)), production rate of insulin (S(2)), feedback effect of insulin on glucose (S(3)), and pharmacodynamic parameters for potassium did not differ by diplotype or sex. CONCLUSIONS: The beta(2) receptor diplotype influences receptor-stimulated glucose production in healthy, nonobese individuals, which is consistent with beta(2) receptor-mediated hepatic glycogenolysis. Future metabolic studies of this system should consider beta(2) receptor genetic variants.

Adolescent↗
PubMed2004

Interactions of prednisolone and other immunosuppressants used in dual treatment of systemic lupus erythematosus in lymphocyte proliferation assays.

Systemic lupus erythematosus is an autoimmune disease primarily affecting women. Currently, systemic lupus erythematosus therapy is suboptimal due to adverse effects of immunosuppressants, particularly corticosteroids. This study determines the single effects of prednisolone, dehydroepiandrosterone, bromocriptine, tamoxifen, mycophenolic acid, 2-chloro-2'-deoxyadenosine, azathioprine, and chloroquine on lectin-stimulated proliferation of human T lymphocytes, as well as determining whether there are interactions in the joint effects of prednisolone and these agents. The T lymphocytes from the whole blood of 10 middle-aged women were stimulated by phytohemagglutinin and cultured with varying drug concentrations. The Hill function was used to evaluate single-drug response data. Isobolograms were constructed to qualitatively analyze interactions. Parametric analysis based on competitive and noncompetitive interaction models was further applied to quantify the joint interactions and predict steroid-sparing potential. The surface interaction parameter (psi) estimated from parametric analysis was in concordance with isobolographic inspection for all interactions studied. All interactions favored the noncompetitive model. Results suggest that dehydroepiandrosterone is additive in its effect with prednisolone, whereas tamoxifen interacts synergistically, both providing steroid-sparing effects. Novel immuno-suppressants such as mycophenolic acid may still provide added pharmacologic benefit during therapy despite a slight antagonistic interaction with prednisolone. These studies help rationalize actual or potential use of other drugs with prednisolone in the treatment of systemic lupus erythematosus.

Adult↗
PubMed2004

Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after single and multiple doses in healthy volunteers.

This study describes a pharmacokinetic (PK) model to account for serum recombinant human erythropoietin (rHuEpo) concentrations in healthy volunteers following intravenous (IV) and subcutaneous (SC) dosing; it also characterizes the pharmacodynamics (PD) of SC rHuEpo effects on reticulocytes, red blood cells (RBC), and hemoglobin (Hb) in blood. Data were obtained from 4 clinical studies carried out in healthy volunteers. Epoetin alfa (rHuEpo) was administered as 5 single IV doses ranging from 10 to 500 IU/kg, as 8 single SC doses ranging from 300 to 2400 IU/kg, and as 2 multiple SC dosage regimens (150 IU/kg/3 times a week [tiw] and 600 IU/kg/wk). A dual-absorption rate model (fast zero-order and slow first-order inputs) with nonlinear disposition characterized the PK of SC rHuEpo. A high K(m) value was obtained indicating that clearance was mildly nonlinear. Absorption was slow (t(max) approximately 24 hours), and the bioavailability of SC rHuEpo increased with dose (ranging from 46%-100%). A catenary cell production and loss model with a feedback down regulation component was used to fit the reticulocyte data yielding estimates of the stimulatory capacity (S(max)), sensitivity (SC(50)), and life span parameters. These parameters were used for simulations of RBC and Hb profiles. An SC(50) of 27 to 61 IU/L was estimated indicating that low physiological plasma rHuEpo concentrations were sufficient to produce pharmacological effects. No marked sex-dependent differences in clinical responses to rHuEpo therapy were found despite baseline differences. Realistic pharmacokinetic and physiological models accounted for clinical responses from a wide array of dosing conditions with rHuEpo. The rationale for greater efficacy of SC administration of rHuEpo compared to IV was ascertained.

Algorithms↗
PubMed2004

The genomic response of skeletal muscle to methylprednisolone using microarrays: tailoring data mining to the structure of the pharmacogenomic time series.

High-throughput data collection using gene microarrays has great potential as a method for addressing the pharmacogenomics of complex biological systems. Similarly, mechanism-based pharmacokinetic/pharmacodynamic modeling provides a tool for formulating quantitative testable hypotheses concerning the responses of complex biological systems. As the response of such systems to drugs generally entails cascades of molecular events in time, a time series design provides the best approach to capturing the full scope of drug effects. A major problem in using microarrays for high-throughput data collection is sorting through the massive amount of data in order to identify probe sets and genes of interest. Due to its inherent redundancy, a rich time series containing many time points and multiple samples per time point allows for the use of less stringent criteria of expression, expression change and data quality for initial filtering of unwanted probe sets. The remaining probe sets can then become the focus of more intense scrutiny by other methods, including temporal clustering, functional clustering and pharmacokinetic/pharmacodynamic modeling, which provide additional ways of identifying the probes and genes of pharmacological interest.

Adrenalectomy↗
PubMed2004

The influence of St. John's wort on the pharmacokinetics and protein binding of imatinib mesylate.

STUDY OBJECTIVE: To determine the effect of St. John's wort on the pharmacokinetics of imatinib mesylate. DESIGN: Open-label, complete crossover, fixed-sequence, pharmacokinetic study. SETTING: Clinical research center. SUBJECTS: Ten healthy adult volunteers. INTERVENTION: Single 400-mg oral doses of imatinib were administered before and after 2 weeks of treatment with St. John's wort 300 mg 3 times/day. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of imatinib were significantly altered by St. John's wort, with reductions of 32% in the median area under the concentration-time curve from time zero to infinity (p=0.0001), 29% in maximum observed concentration (p=0.005), and 21% in half-life (p=0.0001). Protein binding ranged from 97.7-90.3% (mean 94.9%), was concentration independent, and was not altered by St. John's wort. Therapeutic outcomes of imatinib have been shown to correlate with both dose and drug concentrations. CONCLUSION: Coadministration of imatinib with St. John's wort may compromise imatinib's clinical efficacy.

Administration, Oral↗