Pharmacokinetic modelling of serum and bronchial concentrations for clarithromycin and telithromycin, and site-specific pharmacodynamic simulation for their dosages.

WHAT IS KNOWN AND OBJECTIVE: Clinical pharmacokinetic profiles of clarithromycin and telithromycin in bronchopulmonary sites have not been fully characterized. This study aimed to describe in more detail the pharmacokinetics of the two macrolides in epithelial lining fluid (ELF) of human bronchi and to evaluate their pharmacodynamic target attainment at this site. METHODS: Previously reported drug concentration data for serum and ELF were simultaneously fitted to a three-compartment pharmacokinetic model using nonmem program. The model parameter estimates were used for site-specific pharmacodynamic simulation. RESULTS AND DISCUSSION: Population mean parameters for clarithromycin were as follows: distribution volumes of central, peripheral and ELF compartments (V1 /F, V2 /F and V3 /F) = 204·7, 168·9 and 67·1 L; clearance (CL/F) = 34·4 L/h; absorption rate constant (Ka ) = 0·680 1/h; transfer rate constants connecting compartments (K12 , K21 , K13 and K31  = 0·0193, 0·434, 0·667 and 0·260 1/h, respectively). Mean parameters for telithromycin were as follows: V1 /F, V2 /F and V3 /F = 370·3, 290·3 and 213·8 L; CL/F = 89·5 L/h; Ka  = 0·740 1/h; K12 , K21 , K13 and K31  = 0·0026, 1·044, 0·758 and 0·158 1/h, respectively. Using these parameters, the mean ELF/serum ratio in the area under drug concentration-time curve (AUC) was 7·80 for clarithromycin and 8·05 for telithromycin. Clarithromycin achieved a ≥ 90% probability of attaining a pharmacodynamic target [AUC/minimum inhibitory concentration (MIC) = 100] in ELF against bacterial isolates for which MICs were ≤0·5 and ≤1 mg/L for twice-daily doses of 250 and 500 mg, respectively. For telithromycin, once-daily doses of 600 and 800 mg achieved a ≥90% probability in ELF against Streptococcus pneumoniae, Staphylococcus aureus and Moraxella catarrhalis isolates but not Haemophilus influenzae isolates. WHAT IS NEW AND CONCLUSION: These results should provide a better understanding of the bronchial pharmacokinetics of clarithromycin and telithromycin, while also providing useful information about their dosages for respiratory tract infections based on site-specific pharmacodynamic evaluation. Further studies in a large number of patients are needed to confirm our findings and clarify their therapeutic implications.

Comparison of skin permeability for three diclofenac topical formulations: an in vitro study.

Diclofenac is a hydrophilic non-steroidal anti-inflammatory drug (NSAID) widely used in humans and animals. There are limited published studies evaluating diclofenac's skin permeation following topical administration. The aim of our study was to evaluate and compare the in vitro permeation of three different diclofenac-containing formulations (patch, gel, solution) over 24 hours. These formulations were applied (n = 6 per formulation) to pig skin sandwiched between the two chambers in a static Franz diffusion cell and aliquots from the receptor medium were sampled at pre-defined time points. An HPLC method with UV detection was developed and validated with the aim of characterizing the transepidermal penetration in the in vitro system. Using this assay to determine the permeation parameters, results at 24 hours showed that the Flector patch released the highest drug amount (54.6%), whereas a lower drug amount was delivered with the Voltaren Emulgel (38.2%) and the solution (34.4%). The commercial gel showed the highest flux (39.9 +/- 0.9 microg/cm2/h) and the shortest lag-time (1.97 +/- 0.02 h). Based on these in vitro results using pig skin, the transdermal patch resulted in a long-lasting controlled release of diclofenac, while the gel had the shortest lag-time.

Plasma and dermal pharmacokinetics of terpinen-4-ol in rats following intravenous administration.

Terpinen-4-ol, a naturally occurring monoterpene, has been shown to possess antibacterial, antioxidant and anti-inflammatory activities. Furthermore, recent reports have demonstrated that terpinen-4-ol could be developed as new therapies against melanoma either in systemic administration or targeted drug delivery. The purpose of this study was to investigate the pharmacokinetics of terpinen-4-ol in rat plasma and dermal tissue following intravenous (i.v.) bolus injection of terpinen-4-ol at a dose of 2 mg/kg. Unbound concentrations of terpinen-4-ol in dermis were continuously determined by dermal microdialysis. Simultaneously, a conventional blood sampling was performed. The concentrations of terpinen-4-ol in plasma and microdialysates were determined by validated gas chromatography-mass spectrometry. Following i.v. bolus administration, terpinen-4-ol rapidly distributed into the dermis and reached relatively low levels with an average maximum concentration (Cmax) of 0.10 +/- 0.06 microg/ml in comparison with a plasma Cmax of 6.30 +/- 1.90 microg/ml. The free terpinen-4-ol concentrations in dermal tissue were lower than the corresponding total and free plasma concentrations for the entire length of study, indicating that plasma levels do not provide information of actual terpinen-4-ol concentrations in the skin. This study demonstrates that dermal microdialysis is an effective and minimally invasive tool to evaluate the dermal pharmacokinetics of terpinen-4-ol following systemic administration.

Population pharmacokinetics of steady-state carbamazepine in Egyptian epilepsy patients.

WHAT IS KNOWN AND OBJECTIVE: Individualization of carbamazepine (CBZ) dosage regimen in patients with epilepsy based on based on therapeutic drug monitoring (TDM) followed by estimation of pharmacokinetic (PK) parameters can help in better control of epilepsy. Our objective was to establish a population (POP) PK model of CBZ for Egyptian adult and pediatric patients with epilepsy. METHOD: Single steady-state (SS) trough plasma concentrations of CBZ were available for 302 patients with epilepsy (55·6% men and 44·4% women) who were categorized as children (n = 118) and adults (n = 184) with mean age (years) ± SD of 10·6 ± 4·8 and 29·4 ± 9·9, respectively. Carbamazepine was given as an oral suspension (n = 19) or controlled release tablet (n = 283) with average dose of 15·0 ± 7·8 mg/kg per day. A one-compartment model with first-order absorption and elimination for SS conditions (ADVAN2, SS2, TRANS2) was applied using NONMEM 6.2. Separate absorption rate constants were modelled for the two formulations. The mean POP CL, its intersubject variability (ISV), as well as residual error of CBZ concentration were estimated. RESULTS AND DISCUSSION: The POP estimate for CL was 3·5 L/h with coefficient of variation value of 2·6%, which was consistent with literature data. The ISV on CL was 44·5%. The POP PK model was validated by bootstrap re-sampling, and the individual estimates were within the 95% CI of the bootstrap results. Different covariates that might affect CBZ CL have been evaluated but the limited number of samples per individual prevented precise covariate analysis. WHAT IS NEW AND CONCLUSION: The POP PK model we have developed for CBZ shows good predictive performance in Egyptian adult and pediatric patients with epilepsy. Another PK study to better define the effect of different covariates would improve on the model for dosage individualization.

Pharmacokinetics of cefpodoxime in plasma and subcutaneous fluid following oral administration of cefpodoxime proxetil in male beagle dogs.

Pharmacokinetics of cefpodoxime in plasma (total concentration) and subcutaneous fluid (free concentration using microdialysis) was investigated in dogs following single oral administration of prodrug cefpodoxime proxetil (equivalent to 5 and 10 mg/kg of cefpodoxime). In a cross over study design, six dogs per dose were utilized after a 1 week washout period. Plasma, microdialysate, and urine samples were collected upto 24 h and analyzed using high performance liquid chromatography. The average maximum concentration (C(max) ) of cefpodoxime in plasma was 13.66 (±6.30) and 27.14 (±4.56) µg/mL with elimination half-life (t(1/2) ) of 3.01 (±0.49) and 4.72 (±1.46) h following 5 and 10 mg/kg dose, respectively. The respective average area under the curve (AUC(0-∞) ) was 82.94 (±30.17) and 107.71 (±30.79) µg·h/mL. Cefpodoxime was readily distributed to skin and average free C(max) in subcutaneous fluid was 1.70 (±0.55) and 3.06 (±0.93) µg/mL at the two doses. Urinary excretion (unchanged cefpodoxime) was the major elimination route. Comparison of subcutaneous fluid concentrations using pharmacokinetic/pharmacodynamic indices of fT(>MIC) indicated that at 10 mg/kg dose; cefpodoxime would yield good therapeutic outcome in skin infections for bacteria with MIC(50) upto 0.5 µg/mL while higher doses (or more frequent dosing) may be needed for bacteria with higher MICs. High urine concentrations suggested cefpodoxime use for urinary infections in dogs.

Pharmacokinetic/pharmacodynamic model-based combination therapy approach to target antibiotic resistant populations emerged from ciprofloxacin exposure.

BACKGROUND: Despite decades of antimicrobial usage, the relationship between antimicrobial drugs and the development of drug resistance has not been fully delineated. This has led to increased frequency of resistance with increased usage of antimicrobials. In recent years, new insights into the mechanisms of antibiotic resistance have been proposed, leading to a re-evaluation of novel pharmacokinetic/pharmacodynamic (PK/PD) models. We have developed a semi-mechanistic PK/PD model to describe drug-bacteria kill curve relationships using the compensatory mutation hypothesis. In addition, we explored the model-based combination therapy approach to combat the resistance population. METHODS: In vitro kill-curves of E. coli 204 up to 48 h following initial ciprofloxacin (CIP) treatment at 0.0, 0.1, 0.2, 0.5, 1.0, 2.0, 4.0, 8.0, 16.0, 32.0 and 125 times the minimum inhibitory concentration (MIC) totaling 193 data points were obtained with an in vitro system with a simulated CIP half-life of 4 h. The proposed antibiotic resistant mechanism mimics the sequential compensatory mutation hypothesis, in which mutations that acquire drug resistant traits are associated with fitness costs. Subsequent restoration of bacterial fitness is necessary for the population to be clinically relevant. Model parameters were estimated from simultaneous fitting of eleven dose groups using Adapt II software. Standard goodness of fit criteria used to obtain the final model included model convergence, Schwartz Criterion, Akaike Information Criterion, residuals versus predicted concentrations and time, and visual inspection. RESULTS/CONCLUSIONS: The eleven E. coli kill curves after CIP treatment were well described simultaneously by the compensatory mutation model. The emergence of bacterial population with drug resistance characteristics and bacterial fitness restored appears to dominate shortly following CIP treatment. The model suggests a subsequent dose of a different mechanisms of action should be considered for the emerged resistant population.

Influence of the Duffy antigen on pharmacokinetics and pharmacodynamics of recombinant monocyte chemoattractant protein (MCP-1, CCL-2) in vivo.

Monocyte chemoattractant protein-1 (MCP-1, CCL-2) binds to the Duffy antigen (DARC) on red blood cells, which act as a sink for several chemokines including MCP-1. In this study it is hypothesized that DARC may alter the pharmacokinetics of infused recombinant human MCP-1 (rhMCP-1). The primary aim of this first in man trial is to compare the pharmacokinetics of rhMCP-1 in Duffy positive and negative individuals. A randomized, double-blinded, placebo-controlled dose escalation trial was conducted on 36 healthy volunteers. Subjects received infusions of 0.02-2.0 microg/kg rhMCP-1 or placebo for one hour. RhMCP-1 displayed linear pharmacokinetics. Duffy negative individuals reached maximal plasma levels significantly earlier, but overall plasma concentration profiles were not altered. rhMCP-1 markedly increased monocyte counts, and estimated EC50 values were 10-fold higher in Duffy positive than in Duffy negative subjects. Increased monocyte counts were associated with decreased surface expression of intercellular adhesion molecule 1 (ICAM-1, CD54). In contrast, neither CCR-2 or CD11b expression, nor markers of platelet or endothelial activation, inflammation and coagulation were altered. RhMCP-1 is a highly selective chemoattractant for monocytes in humans. The Duffy antigen only minimally alters the pharmacokinetics of rhMCP-1 for doses up to 2 microg/kg.

A model-based analysis of pharmacokinetic-pharmacodynamic (PK/PD) indices of avibactam against Pseudomonas aeruginosa.

OBJECTIVE: The aim of the present work was to use a semi-mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model developed from in vitro time-kill measurements with P. aeruginosa to compare different pharmacodynamic indices derived from simulated human avibactam exposures, with respect to their degree of correlation with the modelled bacterial responses. METHODS: A mathematical model of the effect of ceftazidime-avibactam on the growth dynamics of P. aeruginosa was used to simulate bacterial responses to modelled human exposures from fractionated avibactam dosing regimens with a fixed ceftazidime dosing regimen (2 or 8 g q8h as a 2-h infusion). The relatedness of the 24-h change in bacterial density and avibactam exposure parameters was evaluated to determine exposure parameter that closely correlated with bacterial growth/killing responses. RESULTS: Frequent dosing was associated with higher efficacy, resulting in a reduction of avibactam daily dose. The best-fit PD index of avibactam determined from the simulation was fT > CT of 1 mg/L avibactam and q8h was the longest dosing interval able to achieve 2-log kill: 41-87% (3.3 h to 7.0 h out of 8-h interval, respectively). The avibactam exposure magnitude required to achieve a 2-log kill in the simulations was dependent on the susceptibility of the bacterial isolate to ceftazidime. CONCLUSIONS: Avibactam activity in combination with ceftazidime against multidrug resistant P. aeruginosa correlated with fT > CT. Setting a threshold avibactam concentration to 1 mg/L, superimposed over a simulated human-like exposure of ceftazidime, achieved at least 2-log kill for the clinical dose of 500 mg q8h avibactam as a 2-h infusion, depending on the minimum inhibitory concentration of ceftazidime alone.

Towards precision dosing of vancomycin: a systematic evaluation of pharmacometric models for Bayesian forecasting.

OBJECTIVES: Vancomycin is a vital treatment option for patients suffering from critical infections, and therapeutic drug monitoring is recommended. Bayesian forecasting is reported to improve trough concentration monitoring for dose adjustment. However, the predictive performance of pharmacokinetic models that are utilized for Bayesian forecasting has not been systematically evaluated. METHOD: Thirty-one published population pharmacokinetic models for vancomycin were encoded in NONMEM®7.4. Data from 292 hospitalized patients were used to evaluate the predictive performance (forecasting bias and precision, visual predictive checks) of the models to forecast vancomycin concentrations and area under the curve (AUC) by (a) a priori prediction, i.e., solely by patient characteristics, and (b) also including measured vancomycin concentrations from previous dosing occasions using Bayesian forecasting. RESULTS: A priori prediction varied substantially-relative bias (rBias): -122.7-67.96%, relative root mean squared error (rRMSE) 44.3-136.8%, respectively-and was best for models which included body weight and creatinine clearance as covariates. The model by Goti et al. displayed the best predictive performance with an rBias of -4.41% and an rRMSE of 44.3%, as well as the most accurate visual predictive checks and AUC predictions. Models with less accurate predictive performance provided distorted AUC predictions which may lead to inappropriate dosing decisions. CONCLUSION: There is a diverse landscape of population pharmacokinetic models for vancomycin with varied predictive performance in Bayesian forecasting. Our study revealed the Goti model as suitable for improving precision dosing in hospitalized patients. Therefore, it should be used to drive vancomycin dosing decisions, and studies to link this finding to clinical outcomes are warranted.

Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications.

Intranasal corticosteroids (INSs) are effective treatments for allergic rhinitis, rhinosinusitis, and nasal polyposis. In recent years, increased understanding of corticosteroid and glucocorticoid receptor pharmacology has enabled the development of molecules designed specifically to achieve potent, localized activity with minimal risk of systemic exposure. Pharmacologic potency studies using affinity and other assessments have produced similar rank orders of potency, with the most potent being mometasone furoate, fluticasone propionate, and its modification, fluticasone furoate. The furoate and propionate ester side chains render these agents highly lipophilic, which may facilitate their absorption through nasal mucosa and uptake across phospholipid cell membranes. These compounds demonstrate negligible systemic absorption. Systemic absorption rates are higher among the older corticosteroids (flunisolide, beclomethasone dipropionate, triamcinolone acetonide, and budesonide), which have bioavailabilities in the range of 34-49%. Studies, including 1-year studies with mometasone furoate, fluticasone propionate, and budesonide that evaluated potential systemic effects of INSs in children have generally found no adverse effects on hypothalamic-pituitary-adrenal axis function or growth. Clinical data suggest no significant differences in efficacy between the INSs. Theoretically, newer agents with lower systemic availability may be preferable, and may come closer to the pharmacokinetic/pharmacologic criteria for the ideal therapeutic choice.

Estimation of lithium clearance from routine clinical data in Egyptian bipolar patients. A population pharmacokinetic approach.

Population pharmacokinetics (PK) of lithium as a mood stabilizer was investigated in Egyptian patients with bipolar affective disorders (n = 50) of whom 31 were suffering from lithium toxicity. The mean (+/- SD) age and body weight of patients were 33 +/- 10 years and 67 +/- 3.6 kg, respectively. Patients selected were maintained on lithium carbonate controlled release tablets at doses of 400 mg/12 hours (n = 43) or 200 mg/12 hours (n = 7) respectively. In 19 patients who continued lithium therapy, 1 blood sample/patient was withdrawn for lithium level determination before the morning dose of the drug was given while for 31 patients who suffered from lithium-related toxicity and cessation of drug intake was therapeutically decided, a single blood was drawn at variable time (36, 48 or 72 h) following the last administered dose of the drug. The data was subjected to population PK analysis using NONMEM and a two-compartment model was used. Due to single point sparse data, not all parameters and their between subject variability (BSV) could be determined. Therefore, lithium clearance (CL) and BSV were estimated while other PK parameters were fixed using available literature information. First order (FO) estimation method was used in the analysis. Covariates were evaluated by univariate analysis using likelihood ratio test. The most significant covariate on lithium CL was found to be creatinine clearance (CrCL). The population CL of lithium in the final model was expressed as CLpop = 0.51 x (CrCL/105.3)0.44. The final population PK parameters estimates of lithium were: CL = 0.51 l/h with 12.7% BSV, V1 (Fixed) = 15.2 l, Q (Fixed) = 7.44 l/h, and V2 (Fixed) = 6.7 l. The mean value of lithium concentration at 12 hours as predicted by the final model in the patients with drug toxicity was 1.3 +/- 0.1 mmol/l versus 0.8 +/- 0.14 mmol/l in patients without toxic signs. External validation of the final model on another group of adult bipolar patients (n = 12) maintained on lithium therapy showed a predictive ability of -35 to 65% as represented by% error for the predictions.

Experimental design and modelling approach to evaluate efficacy of ß-lactam/ß-lactamase inhibitor combinations.

BACKGROUND: A ß-lactamase inhibitor (BLI) confers susceptibility of ß-lactamase-expressing multidrug resistant (MDR) organisms to the partnering ß-lactam (BL). AIMS: To discuss the experimental design and modelling strategies for two-drug combinations, using ceftazidime- and aztreonam-avibactam combinations, as examples. SOURCES: The information came from several publications on avibactam in vitro time-kill studies and corresponding pharmacodynamic models. CONTENT: The experimental design to optimally gather crucial information from constant-concentration time-kill studies is to use an agile matrix of two-drug concentration combinations that cover 0.25- to 4-fold BL minimum inhibitory concentration (MIC) relative to the BLI concentrations to be tested against the particular isolate. This shifting agile design can save substantial costs and resources, without sacrificing crucial information needed for model development. The complex synergistic BL/BLI interaction is quantitatively explored using a semi-mechanistic pharmacokinetic-pharmacodynamic (PK/PD) mathematical model that accounts for antimicrobial activities in the combination, bacteria-mediated BL degradation and inhibition of BL degradation by BLI. A predictive mathematical formulation for the two-drug killing effects preserves the correlation between the model-derived EC50 of BL and the BL MIC. The predictive value of PK/PD model is evaluated against external data that were not used for model development, including but not limited to in vitro hollow fibre and in vivo murine infection models. IMPLICATIONS: As a framework for translational predictions, the goal of this modelling strategy is to significantly decrease the decision-making time by running clinical trial simulations with MIC-substituted EC50 function for isolates of comparable susceptibility through established correlation between BL MIC and EC50 values.

Biowaiver monographs for immediate release solid oral dosage forms: prednisolone.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisolone are reviewed. Data on its solubility, oral absorption, and permeability are not totally conclusive, but strongly suggest a BCS Class 1 classification. Prednisolone's therapeutic indications and therapeutic index, pharmacokinetics, and the possibility of excipient interactions were also taken into consideration. Available evidence indicates that a biowaiver for IR solid oral dosage forms formulated with the excipients tabulated in this article would be unlikely to expose patients to undue risks.

Biowaiver monographs for immediate release solid oral dosage forms: prednisone.

Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing prednisone are reviewed. Due to insufficient data prednisone cannot be definitively classified according to the current Biopharmaceutics Classification System (BCS) criteria as both the solubility and the permeability of prednisone are on the borderline of the present criteria of BCS Class I. Prednisone's therapeutic indications and therapeutic index, pharmacokinetics and the possibility of excipient interactions were also taken into consideration. Available evidence indicates that a biowaiver for IR solid oral dosage forms formulated with the excipients tabulated in this article would be unlikely to expose patients to undue risks.

Prediction of in vivo and in vitro infection model results using a semimechanistic model of avibactam and aztreonam combination against multidrug resistant organisms.

The combination of aztreonam-avibactam is active against multidrug-resistant Enterobacteriaceae that express metallo-ß-lactamases. A complex synergistic interaction exists between aztreonam and avibactam bactericidal activities that have not been quantitatively explored. A two-state semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) logistic growth model was developed to account for antimicrobial activities in the combination of bacteria-mediated degradation of aztreonam and the inhibition of aztreonam degradation by avibactam. The model predicted that changing regimens of 2 g aztreonam plus 0.375 and 0.6 g avibactam as a 1-hour infusion were qualitatively similar to that observed from in vivo murine thigh infection and hollow-fiber infection models previously reported in the literature with 24-hour log kill ≥1. The current approach to characterize the effect of avibactam in enhancing aztreonam activity from time-kill study was accomplished by shifting the half-maximal effective concentration (EC50 ) of aztreonam in increasing avibactam concentration using a nonlinear equation as a function of avibactam concentration, providing a framework for translational predictions.

Grapefruit-drug interactions: can interactions with drugs be avoided?

Grapefruit is rich in flavonoids, which have been demonstrated to have a preventive influence on many chronic diseases, such as cancer and cardiovascular disease. However, since the early 1990s, the potential health benefits of grapefruit have been overshadowed by the possible risk of interactions between drugs and grapefruit and grapefruit juice. Several drugs interacting with grapefruit are known in different drug classes, such as HMG-CoA reductase inhibitors, calcium antagonists, and immunosuppressives. Currently known mechanisms of interaction include the inhibition of cytochrome P450 as a major mechanism, but potential interactions with P-glycoprotein and organic anion transporters have also been reported. This review is designed to provide a comprehensive summary of underlying mechanisms of interaction and human clinical trials performed in the area of grapefruit drug interactions and to point out possible replacements for drugs with a high potential for interactions.

HPLC determination of dexamethasone in human plasma and its application to an in vitro release study from endovascular stents.

A simple, accurate and precise HPLC assay was developed and validated for determination of dexamethasone in human plasma. Triamcinolone acetonide was used as internal standard (I.S.) and plasma samples were extracted using liquid-liquid extraction with ethyl acetate. Chromatography was performed on a C-18 column with acetonitrile-triple distilled water (28:72% v/v, pH adjusted to 2.3 with phosphoric acid) at a flow rate of 1.2 mL/min and detection wavelength 254 nm. The assay was linear at a concentration range of 0.25-6 microg/mL with recoveries >77%. Precision and accuracy were within the acceptable limits. The method was used to determine dexamethasone release from different material coated endoluminal vascular stents in in vitro human plasma experiments. The results were useful in identifying a good coating material for the stents.

Interpretation of absorption rate data for inhaled fluticasone propionate obtained in compartmental pharmacokinetic modeling.

OBJECTIVE: Reports characterizing the pharmacokinetics of inhaled fluticasone propionate (FP) using compartmental approaches have suggested that the absorption of FP into the systemic circulation is rapid with a half-life of approximately 10 min. We believe that this is a classical case of misassignment of the pharmacokinetic parameter estimates, a problem often encountered while modeling pharmacokinetic data. The objective of this study was to illustrate and analyze this problem using actual blood level data of FP obtained in 14 healthy subjects. MATERIALS AND METHODS: Serum concentration-time data of FP were obtained from a double-blind, randomized study involving single and multiple twice-daily inhalations of 500 microg via a dry powder device, Diskus. The profiles were fitted using one- and two-compartment pharmacokinetic models with first order absorption. Various permutations of the resulting exponential rate constants were analyzed to determine the combination that was most consistent with the underlying physical process. RESULTS: The two-compartment body model with first order absorption gave excellent fits for the observed FP concentrations after both single and multiple dosing. Even though peak levels were reached relatively early (30 - 90 min) after inhalation, the combination that most appropriately described the underlying process was alpha > Ka > beta, i.e. slow absorption, rapid distribution and slower elimination kinetics. The absorption, distribution and elimination half-lives resulted to be 3.8 h, 9.9 min and 13.6 h, respectively, consistent with the high lipophilicity and sustained dissolution characteristics observed in vitro. CONCLUSIONS: Analysis of FP pharmacokinetics after inhalation represents a classical case of potential misassignment of the exponential rate constants, which if ignored, could lead to erroneous interpretations regarding the underlying process. The study also elucidates the pitfall of using t(max) to calculate absorption rate.

Microdialysis in peripheral tissues.

The objective of this review is to survey the recent literature regarding the applications of microdialysis in pharmacokinetic studies and facilitating many other studies in peripheral tissues such as muscle, subcutaneous adipose tissue, heart, lung, etc. It has been reported extensively that microdialysis is a useful technique for monitoring free concentrations of compounds in extracellular fluid (ECF), and it is gaining popularity in pharmacokinetic and pharmacodynamic studies, both in experimental animals and humans. The first part of this review discusses the use of microdialysis technique for ECF sampling in peripheral tissues in animal studies. The second part of the review describes the use of microdialysis for ECF sampling in peripheral tissues in human studies. Microdialysis has been applied extensively to measure both endogenous and exogenous compounds in ECF. Of particular benefit is the fact that microdialysis measures the unbound concentrations in the peripheral tissue fluid which have been shown to be responsible for the pharmacological effects. With the increasing number of applications of microdialysis, it is obvious that this method will have an important place in studying drug pharmacokinetics and pharmacodynamics.

Desensitization of brain opiate receptor mechanisms by gonadal steroid treatments that stimulate luteinizing hormone secretion.

We studied the effects of two ovarian steroid treatments that induce proestrous-like surges in LH secretion on responsiveness to morphine sulfate (MS), as measured by induced hypothermic, antinociceptive, behavioral, and LH secretory changes. Ovariectomized rats received no steroids (OVX), 7.5 micrograms estradiol benzoate 2 days before the experiment (EB), or EB and then 5 mg progesterone 48 h later (EBP). MS administration coincided with the steroid-induced LH hypersecretion that occurs in the EB and EBP rats at 1530-1630 h. Serum LH concentrations were determined 30 min after administration of MS. In OVX and EB rats, MS caused a dose-dependent decrease in serum LH, but even 20 mg/kg MS did not alter serum LH during the EBP-induced LH surge. Brain-mediated morphine-induced analgesia was evaluated in the three steroid treatment groups from measurement of latency to pawlick on a hot plate. EB and EBP rats were less responsive than OVX rats to MS-induced antinociception. EB and EBP rats were also less responsive than OVX animals to the spinal cord-mediated analgesia due to MS, as calculated by tail-flick latency. MS-induced hypothermia revealed a responsiveness order of OVX greater than EB greater than EBP. Whereas MS caused a dose-dependent reduction in locomotor activity in OVX and EB rats, EBP rats showed marked hyperactivity at low MS doses and were less responsive to the suppression of locomotor activity at higher doses. These marked steroid-induced changes in MS responsiveness could not be explained by altered pharmacokinetic disposition of morphine. These data indicate that treatment with EBP, which stimulates a preovulatory-like LH surge, decreases the ability of MS to induce hypothermic, antinociceptive, and behavioral responses and abolishes its capacity to suppress LH release. These effects of gonadal steroids were not observed before the LH surge, which suggests that this surge is linked to the decline in MS sensitivity. Further, the diminished response to MS appears to be a function of the magnitude of the LH surge.