Subject(s)
Biomarkers/blood , Latent Tuberculosis/blood , Lipids/blood , Adolescent , Adult , Antibiotics, Antitubercular/administration & dosage , Antitubercular Agents/administration & dosage , Apolipoproteins A/metabolism , Apolipoproteins B/metabolism , Female , Humans , Isoniazid/administration & dosage , Latent Tuberculosis/diagnosis , Lipid Metabolism , Male , Middle Aged , Rifampin/administration & dosage , Young AdultABSTRACT
Synergism between gemfibrozil and CDD 3540, drugs used to elevate mouse serum HDL cholesterol and apoprotein A1, is modeled using nonlinear response surface techniques. This approach employs a common simple pharmacological model to describe the dose-response function. Its parameters are modeled as functions of drug mixture fractions using models borrowed from mixture experiment analysis methods. This study advances previous in vitro synergy studies in three key areas. First, it was in vivo, with the associated additional variability. Second, the sample size was much smaller than in previous studies. Finally, this was the first specially designed study with this type of statistical analysis in mind. The design consisted of replicated observations along each of five rays at combination amounts chosen employing the principles of D-optimality. Also, the observed in vivo synergism of the combined use of these drugs, elevated levels of HDL-C and apoA1, and the experimental results and statistical models may provide important clues regarding the biological mechanisms of action of the two compounds.
Subject(s)
Apolipoprotein A-I/metabolism , Cholesterol, HDL/metabolism , Drug Synergism , Gemfibrozil/pharmacology , Imidazoles/pharmacology , Models, Biological , PPAR alpha/agonists , Receptors, Steroid/agonists , Animals , Dose-Response Relationship, Drug , Male , Mice , Pregnane X ReceptorABSTRACT
The authors designed 2 randomized controlled studies to examine the effects of etoricoxib 60 to 120 mg daily on methotrexate pharmacokinetics in 50 rheumatoid arthritis (RA) patients on stable doses of methotrexate (7.5-20 mg). Patients received oral methotrexate at baseline and on days 7 and 14. In study 1, patients received etoricoxib 60 mg (days 1-7) and then 120 mg (days 8-14); in study 2, patients received etoricoxib 90 mg (days 1-7) and then 120 mg (days 8-14). For study 1, the AUC(0-infinity) geometric mean ratio (GMR) (90% confidence interval [CI]) for day 7 versus baseline was 1.01 (0.91, 1.12) for etoricoxib 60 mg; the area under the plasma concentration-time curve from zero to infinity (AUC(0-infinity)) GMR (90% CI) for day 14 was 1.28 (1.15, 1.42) for etoricoxib 120 mg. For study 2, the AUC(0-infinity) GMR (90% CI) for day 7 versus baseline was 1.07 (1.01, 1.13) for etoricoxib 90 mg; the AUC(0-infinity) GMR (90% CI) for day 14 was 1.05 (0.99, 1.11) for etoricoxib 120 mg. In summary, etoricoxib 60 and 90 mg had no effect on methotrexate plasma concentrations. Although no effect on methotrexate pharmacokinetics was observed with etoricoxib 120 mg in study 2, GMR AUC(0-infinity) fell outside the prespecified bounds in study 1. Standard monitoring of methotrexate-related toxicity should be continued when etoricoxib and methotrexate are administered concurrently, especially with doses >90 mg etoricoxib.
Subject(s)
Antirheumatic Agents/pharmacokinetics , Cyclooxygenase 2 Inhibitors/adverse effects , Drug Therapy, Combination/adverse effects , Methotrexate/pharmacokinetics , Pyridines/adverse effects , Sulfones/adverse effects , Administration, Oral , Adult , Aged , Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/drug therapy , Cyclooxygenase 2 Inhibitors/administration & dosage , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Interactions , Etoricoxib , Female , Humans , Male , Methotrexate/administration & dosage , Middle Aged , Pyridines/administration & dosage , Sulfones/administration & dosageABSTRACT
Very few antagonists have been identified for the human pregnane X receptor (PXR). These molecules may be of use for modulating the effects of therapeutic drugs, which are potent agonists for this receptor (e.g., some anticancer compounds and macrolide antibiotics), with subsequent effects on transcriptional regulation of xenobiotic metabolism and transporter genes. A recent novel pharmacophore for PXR antagonists was developed using three azoles and consisted of two hydrogen bond acceptor regions and two hydrophobic features. This pharmacophore also suggested an overall small binding site that was identified on the outer surface of the receptor at the AF-2 site and validated by docking studies. Using computational approaches to search libraries of known drugs or commercially available molecules is preferred over random screening. We have now described several new smaller antagonists of PXR discovered with the antagonist pharmacophore with in vitro activity in the low micromolar range [S-p-tolyl 3',5-dimethyl-3,5'-biisoxazole-4'-carbothioate (SPB03255) (IC(50), 6.3 microM) and 4-(3-chlorophenyl)-5-(2,4-dichlorobenzylthio)-4H-1,2,4-triazol-3-ol (SPB00574) (IC(50), 24.8 microM)]. We have also used our computational pharmacophore and docking tools to suggest that most of the known PXR antagonists, such as coumestrol and sulforaphane, could also interact on the outer surface of PXR at the AF-2 domain. The involvement of this domain was also suggested by further site-directed mutagenesis work. We have additionally described an FDA approved prodrug, leflunomide (IC(50), 6.8 microM), that seems to be a PXR antagonist in vitro. These observations are important for predicting whether further molecules may interact with PXR as antagonists in vivo with potential therapeutic applications.
Subject(s)
Computational Biology/methods , Drug Design , Receptors, Steroid/antagonists & inhibitors , Cell Line, Tumor , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Ligands , Models, Molecular , Mutagenesis, Site-Directed , Mutant Proteins/metabolism , Pregnane X ReceptorABSTRACT
We have investigated several in silico and in vitro methods to improve our ability to predict potential drug interactions of antibiotics. Our focus was to identify those antibiotics that activate pregnane X receptor (PXR) and induce CYP3A4 in human hepatocytes and intestinal cells. Human PXR activation was screened using reporter assays in HepG2 cells, kinetic measurements of PXR activation were made in DPX-2 cells, and induction of CYP3A4 expression and activity was verified by quantitative polymerase chain reaction, immunoblotting, and testosterone 6beta-hydroxylation in primary human hepatocytes and LS180 cells. We found that in HepG2 cells CYP3A4 transcription was activated strongly (> 10-fold) by rifampin and troleandomycin; moderately (> or = 7-fold) by dicloxacillin, tetracycline, clindamycin, griseofulvin, and (> or = 4-fold) erythromycin; and weakly (> 2.4-fold) by nafcillin, cefaclor, sulfisoxazole, and (> 2-fold) cefadroxil and penicillin V. Similar although not identical results were obtained in DPX-2 cells. CYP3A4 mRNA and protein expression were induced by these antibiotics to differing extents in both liver and intestinal cells. CYP3A4 activity was significantly increased by rifampin (9.7-fold), nafcillin and dicloxacillin (5.9-fold), and weakly induced (2-fold) by tetracycline, sufisoxazole, troleandomycin, and clindamycin. Multiple pharmacophore models and docking indicated a good fit for dicloxacillin and nafcillin in PXR. These results suggest that in vitro and in silico methods can help to prioritize and identify antibiotics that are most likely to reduce exposures of medications (such as oral contraceptive agents) which interact with enzymes and transporters regulated by PXR. In summary, nafcillin, dicloxacillin, cephradine, tetracycline, sulfixoxazole, erythromycin, clindamycin, and griseofulvin exhibit a clear propensity to induce CYP3A4 and warrant further clinical investigation.
Subject(s)
Anti-Bacterial Agents/pharmacology , Cytochrome P-450 CYP3A/biosynthesis , Intestines/drug effects , Liver/drug effects , Receptors, Steroid/agonists , Base Sequence , Cell Line , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , DNA Primers , Enzyme Induction , Genes, Reporter , Humans , In Vitro Techniques , Intestines/enzymology , Liver/enzymology , Pregnane X Receptor , RNA, Messenger/geneticsABSTRACT
The pregnane X receptor (PXR) is an important transcriptional regulator of the expression of xenobiotic metabolism and transporter genes. The receptor is promiscuous, binding many structural classes of molecules that act as agonists at the ligand-binding domain, triggering up-regulation of genes, increasing the metabolism and excretion of therapeutic agents, and causing drug-drug interactions. It has been suggested that human PXR antagonists represent a means to counteract such interactions. Several azoles have been hypothesized to bind the activation function-2 (AF-2) surface on the exterior of PXR when agonists are concurrently bound in the ligand-binding domain. In the present study, we have derived novel computational models for PXR agonists using different series of imidazoles, steroids, and a set of diverse molecules with experimental PXR agonist binding data. We have additionally defined a novel pharmacophore for the steroidal agonist site. All agonist pharmacophores showed that hydrophobic features are predominant. In contrast, a qualitative comparison with the corresponding PXR antagonist pharmacophore models using azoles and biphenyls showed that they are smaller and hydrophobic with increased emphasis on hydrogen bonding features. Azole antagonists were docked into a proposed hydrophobic binding pocket on the outer surface at the AF-2 site and fitted comfortably, making interactions with key amino acids involved in charge clamping. Combining computational and experimental data for different classes of molecules provided strong evidence for agonists and antagonists binding distinct regions on PXR. These observations bear significant implications for future discovery of molecules that are more selective and potent antagonists.
Subject(s)
Receptors, Steroid/agonists , Receptors, Steroid/antagonists & inhibitors , Binding Sites , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Computer Simulation , Genes, Reporter , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Liver Neoplasms/pathology , Luciferases/metabolism , Models, Chemical , Models, Molecular , Molecular Structure , Plasmids , Pregnane X Receptor , Protein Binding , Protein Structure, Tertiary , Receptors, Steroid/chemistry , Receptors, Steroid/metabolism , Transcriptional ActivationABSTRACT
Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.
Subject(s)
Adaptation, Physiological , Biology , Dose-Response Relationship, Drug , Stress, Physiological , Terminology as Topic , Animals , HumansABSTRACT
The possibility that non-sedating antihistamines could elicit sedation in mice due to drug-induced inhibition of brain PgP was evaluated by measuring the ability of desloratadine alone or in combination with verapamil to cause ataxia in mice. Also, the concentrations of desloratadine in plasma and in brain homogenates were measured by liquid chromatography-mass spectrometry. Relative to methylcellulose (control) treatment, verapamil plus desloratadine decreased rotarod performance of mice. Plasma concentrations of desloratadine appeared comparable in the mice treated with either desloratadine or verapamil plus desloratadine, however the rate of decline of desloratadine from brain tissue was slower in mice treated with verapamil plus desloratadine compared to mice treated with desloratadine only. These data suggest that inhibition of brain PgP can convert desloratadine to a sedating antihistamine in mice.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/drug effects , Histamine H1 Antagonists, Non-Sedating/pharmacokinetics , Loratadine/analogs & derivatives , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Ataxia/chemically induced , Brain/metabolism , Chromatography, Liquid , Drug Interactions , Histamine H1 Antagonists, Non-Sedating/adverse effects , Histamine H1 Antagonists, Non-Sedating/pharmacology , Loratadine/adverse effects , Loratadine/pharmacokinetics , Loratadine/pharmacology , Male , Mass Spectrometry , Mice , Mice, Inbred C57BL , Probenecid/pharmacology , Tissue Distribution , Verapamil/pharmacologyABSTRACT
Cryopreserved human hepatocytes in suspension were used to estimate in vivo hepatic clearances for six different drugs. In vitro intrinsic clearances were measured on the basis of substrate depletion. The number of different hepatocyte donors required for a reasonable estimate of in vivo hepatic clearance--within twice or (1/2) of the actual value--was determined. Depending upon the desired level of confidence, anywhere from 9-20 donors are required by this method.
Subject(s)
Hepatocytes/metabolism , Pharmaceutical Preparations/metabolism , Tissue Donors , Cryopreservation , Humans , Models, BiologicalABSTRACT
The use of rat half-life data to predict human half-lives for drugs and other xenobiotics has previously been shown to be of value. Since transgenic and knockout mice are increasingly used in early stages of preclinical drug development, we wondered whether the estimation of half-life values in mice might be used in the same way that has been recommended for rats. A dataset of mouse and human half-life values was assembled for 88 drugs. Three different regression models were then applied to the prediction of human half-life values from mouse values. The results showed that none of the models was superior to any other, and that all models, including the simplest linear regression model, could predict a human half-life value from a mouse half-life value such that there would be an 80% chance that the predicted value would be within three-fold (i.e. between 0.33 times and 3 times) of the actual human value.
Subject(s)
Drug Evaluation, Preclinical/methods , Regression Analysis , Xenobiotics/pharmacokinetics , Animals , Half-Life , Humans , Linear Models , Mice , Mice, Knockout , Mice, Transgenic , Species SpecificityABSTRACT
The in vitro metabolism of the selective M1 muscarinic agonist CDD-0102-J was evaluated in heterologous systems expressing individual human cytochrome P-450 (CYP) isoenzymes and also in suspensions of cryopreserved human hepatocytes. In all experiments, the metabolism of CDD-0102-J was characterized based on its rate of disappearance using an HPLC assay since no metabolites have as yet been characterized. The human CYP isoenzymes used were CYP1A2, 2A6, 2B6, 2C8, 2C19, 2D6, and 3A4. Measurable decreases in CDD-0102-J concentrations over time were detectable only in systems containing either CYP2D6 or CYP2C8, although the unbound in vitro clearance was more than 20 times larger for CYP2D6 (7.6 mL h(-1) nmol(-1)) than for CYP2C8 (0.35 mL h(-1) nmol(-1)). When scaled to in vivo hepatic clearance based on just CYP2D6 and CYP2C8, the projected hepatic clearance for CDD-0102-J was 7.7 L h(-1), which corresponded closely with the hepatic clearance of 8.4 L h(-1) scaled from experiments using cryopreserved human hepatocytes.
Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Hepatocytes/metabolism , Muscarinic Agonists/pharmacokinetics , Oxadiazoles/pharmacokinetics , Pyrimidines/pharmacokinetics , Receptor, Muscarinic M1/agonists , Chromatography, High Pressure Liquid , Cytochrome P-450 Enzyme System/genetics , Hepatocytes/enzymology , Humans , In Vitro Techniques , Isoenzymes/genetics , Isoenzymes/metabolismABSTRACT
OBJECTIVE: Correlations between probabilities of resistance and the frequencies with which antibiotics were prescribed for treating bacterial respiratory infections were examined in a nationwide ambulatory population. STUDY DESIGN AND SETTING: The data of a nationwide probability sample survey of visits to physician offices in the United States in 1999 were used to conduct this study of drug use. A clinical pharmacologist identified antibiotics prescribed during those visits using a large online database. The participating physicians diagnosed the bacterial respiratory infections. An infectious disease expert determined the probabilities of bacterial resistance from a nationwide antibiotic surveillance database. RESULTS: Various bacterial respiratory infections were diagnosed during 6.5% of physician office visits in 1999. One or more antibiotics were prescribed during 51.0% of those visits. The probabilities of resistance to the most frequently prescribed antibiotics varied from 20% to 40% and showed a weak positive correlation with the frequencies of antibiotic prescriptions. CONCLUSION: A significant number of inappropriate antibiotic prescriptions were issued for infections with a high probability of bacterial resistance to the prescribed antibiotics.
Subject(s)
Ambulatory Care/methods , Anti-Bacterial Agents/therapeutic use , Health Care Surveys/methods , Medication Errors/statistics & numerical data , Respiratory Tract Infections/drug therapy , Adolescent , Adult , Age Distribution , Amoxicillin/therapeutic use , Drug Resistance, Bacterial , Female , Humans , Male , Middle Aged , Physicians' Offices , Respiratory Tract Infections/epidemiology , Sex Distribution , United States/epidemiologyABSTRACT
OBJECTIVE: To review the use of inhibitory constants (Ki) determined from in vitro experiments in the prediction of the significance of inhibitory drug-drug interactions (DDIs). DATA SOURCES: Searches of MEDLINE (1966-August 2004) and manual review of journals, conference proceedings, reference textbooks, and Web sites were performed using the key search terms cytochrome P450, drug-drug interaction, inhibition constant, and Ki. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated, and information deemed relevant was included for this review. DATA SYNTHESIS: The cytochrome P450 isoenzymes factor prominently in the explanation of numerous DDIs. Although the regulation of these enzymes by one drug can affect the pharmacokinetics of other drugs, the consequences may not necessarily be significant either in terms of pharmacokinetic or clinical outcomes. Yet, many DDI monographs originate as unconfirmed case reports that implicate the influence of one drug on the CYP-mediated metabolism of another, and these often uncorroborated mechanisms can eventually become regarded as dogma. One consequence of this process is the over-prediction of potentially important DDIs. The pharmaceutical industry, Food and Drug Administration, and pharmaceutical scientists have developed a strategy for predicting the significance of inhibitory DDIs at the earliest possible stages of drug development based on a new chemical entity's Ki value, determined in vitro. CONCLUSIONS: We suggest that the use of Ki values of drugs purported to behave as CYP inhibitors be incorporated in the assessment of case reports that ascribe DDIs to inhibition of metabolism of one drug by another.
Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Drug Evaluation/methods , Drug Interactions , Area Under Curve , Cytochrome P-450 Enzyme Inhibitors , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacokinetics , Enzyme Inhibitors/pharmacology , Humans , Pharmaceutical Preparations/metabolismABSTRACT
INTRODUCTION: Previous publications from GlaxoSmithKline and University of Toledo laboratories convey our independent attempts to predict the half-lives of xenobiotics in humans using data obtained from rats. The present investigation was conducted to compare the performance of our published models against a common dataset obtained by merging the two sets of rat versus human half-life (hHL) data previously used by each laboratory. METHODS: After combining data, mathematical analyses were undertaken by deploying both of our previous models, namely the use of an empirical algorithm based on a best-fit model and the use of rat-to-human liver blood flow ratios as a half-life correction factor. Both qualitative and quantitative analyses were performed, as well as evaluation of the impact of molecular properties on predictability. RESULTS: The merged dataset was remarkably diverse with respect to physiochemical and pharmacokinetic (PK) properties. Application of both models revealed similar predictability, depending upon the measure of stipulated accuracy. Certain molecular features, particularly rotatable bond count and pK(a), appeared to influence the accuracy of prediction. DISCUSSION: This collaborative effort has resulted in an improved understanding and appreciation of the value of rats to serve as a surrogate for the prediction of xenobiotic half-lives in humans when clinical pharmacokinetic studies are not possible or practicable.
Subject(s)
Xenobiotics/pharmacokinetics , Algorithms , Animals , Data Collection , Half-Life , Humans , Liver/blood supply , Mathematics , Predictive Value of Tests , Rats , Statistics as Topic , Toxicity Tests , Xenobiotics/chemistryABSTRACT
Orphan nuclear receptors (ONRs) have been implicated in the regulation of lipids. Several clinical studies conducted either prospectively or epidemiologically have pointed to a link between the regulation of hepatic CYP enzymes and HDL-cholesterol (HDL-C) and/or apolipoprotein A1 (apoA1). The treatment of rats with a series of imidazole inducers of CYP3A yielded correlations between in vitro CYP3A activity measured as erythromycin demethylase activity and plasma HDL-C and hepatic apoA1 mRNA. Similarly, a correlation was established between in vivo CYP3A activity, measured as ethosuximide clearance, and plasma HDL-C and hepatic apoA1 mRNA. The treatment of wild-type (WT) mice with PXR agonists elicited increases in serum HDL-C and serum apoA1 levels. On the other hand, the treatment of PXR-knockout mice (PXR-KOs) with the same PXR agonists failed to elicit increases in either serum HDL-C or serum apoA1 levels. Superposition of the structures of three imidazoles known to be active CYP3A inducers in rats with the human PXR pharmacophore demonstrated a partial fit and predicted EC(50) values typical of weak-moderate hPXR inducers in humans. These imidazoles have been shown to increase apoA1 and HDL-C in rats and mice. Taken together, these data suggest that PXR plays an important role in the regulation of apoA1 and HDL-C in rodents.
Subject(s)
Apolipoprotein A-I/blood , Cholesterol, HDL/blood , Receptors, Cytoplasmic and Nuclear/agonists , Receptors, Cytoplasmic and Nuclear/physiology , Receptors, Steroid/agonists , Receptors, Steroid/physiology , Animals , Clotrimazole/chemistry , Clotrimazole/pharmacology , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Pregnane X Receptor , Rats , Rats, Sprague-Dawley , Receptors, Cytoplasmic and Nuclear/deficiency , Receptors, Steroid/deficiencyABSTRACT
This study was undertaken to determine whether rofecoxib can interfere with CYP1A2 activity in humans using theophylline as a probe substrate. Single oral doses of theophylline were administered to each of three panels of 12 healthy subjects receiving daily doses of rofecoxib for 7 days to examine the effect of rofecoxib administration on the absorption and disposition of theophylline. Each panel was administered doses of 12.5, 25, or 50 mg of rofecoxib or a matching placebo in a two-way, randomized, crossover fashion and administered a single oral 300-mg dose of theophylline on day 7 of rofecoxib or placebo administration. Plasma concentrations of theophylline were monitored for 48 hours postdose to assess differences in pharmacokinetics. All three commercially marketed doses of rofecoxib were found to slow the clearance of theophylline with no detectable effect on absorption. CL/F values for theophylline were estimated from AUC infinity and by point estimates from the concentrations of drug in plasma at 12 and 24 hours postdose. The point estimates of CL/F were found to be in agreement with those derived from AUC.
Subject(s)
Cytochrome P-450 CYP1A2 Inhibitors , Cytochrome P-450 CYP1A2/drug effects , Dose-Response Relationship, Drug , Lactones/metabolism , Lactones/pharmacokinetics , Molecular Probes/drug effects , Theophylline/metabolism , Theophylline/pharmacokinetics , Administration, Oral , Adult , Cross-Over Studies , Cytochrome P-450 CYP1A2/biosynthesis , Double-Blind Method , Humans , Lactones/administration & dosage , Male , Middle Aged , Sulfones , Theophylline/administration & dosageABSTRACT
Growing interest in the prediction of in vivo pharmacokinetic data from purely in vitro data has grown into a process known as the in vitro-in vivo correlation (IVIC). IVIC can be used to determine the viability of new chemical entities in the early drug development phases, leading to a reduction of resource spending by many large pharmaceutical companies. Here, a convective-dispersion model was developed to predict the total hepatic clearance of six drugs using pharmacokinetic data obtained from in vitro metabolism studies in which the drug disappearance from suspensions of human cryopreserved hepatocytes was measured. Predicted in vivo hepatic clearances estimated by the convective-dispersion model were ultimately compared to the actual clearance values and to in vivo hepatic clearances that were scaled based on the well-stirred model. Finally, sensitivity studies were performed to determine the dependence of hepatic clearance on a number of physiological model parameters. Results reaffirmed that low clearance drugs exhibit rate-limited metabolism, and their hepatic clearances are thus independent of blood flow characteristics, whereas drugs with relatively higher clearance values show a more pronounced dependence on the flood flow properties of dispersion and convection. Absent a priori knowledge about the flow-dependent properties of a drug's clearance, the convective dispersion model applied to disappearance data acquired from cryopreserved human hepatocytes is likely to provide satisfactory estimates of hepatic drug clearance.
Subject(s)
Hepatocytes/metabolism , Liver/metabolism , Pharmaceutical Preparations/metabolism , Algorithms , Cryopreservation , Humans , In Vitro Techniques , Models, Biological , Perfusion , Predictive Value of TestsABSTRACT
Some macrolide antibiotics have been shown to produce significant drug-drug interactions through the inhibition of cytochrome P450 (CYP) enzymes. In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A (CSA), a substrate of CYP3A4. The effects of azithromycin on CSA disposition kinetics were evaluated in eight stable renal transplant patients. Patients had been stabilized on individualized doses of CSA which remained unchanged throughout the study. Azithromycin was administered for 3 days. Baseline measurements of CSA disposition kinetics were taken prior to azithromycin treatment (study day 2) and after 3 days (study day 5) of azithromycin treatment (500mg/day, orally). The key parameters of interest were the area under the CSA blood concentration versus time curve (AUC) measured for 24h after the morning dose of CSA on both days 2 and 5, and the C(max) values of CSA. The geometric mean ratios (GMRs) of those parameters (day 5/day 2) and their 90% confidence intervals (90% CI) were 107 (98,116) and 119 (104,136), respectively. The 7% increase in exposure level and 19% increase in peak plasma concentration are not likely to be clinically significant. It is concluded that azithromycin (500mg/dayx3 days) does not alter the disposition kinetics of CSA in a clinically significant way, and that CSA dosage adjustments are not warranted in renal transplant patients taking these two drugs together.
Subject(s)
Anti-Bacterial Agents/pharmacology , Azithromycin/pharmacology , Cyclosporine/pharmacokinetics , Immunosuppressive Agents/pharmacokinetics , Kidney Transplantation/physiology , Anti-Bacterial Agents/therapeutic use , Azithromycin/therapeutic use , Chromatography, Liquid , Cyclosporine/blood , Cyclosporine/therapeutic use , Cytochrome P-450 CYP3A , Cytochrome P-450 Enzyme System/metabolism , Drug Administration Schedule , Female , Fluorescence Polarization Immunoassay , Humans , Immunosuppressive Agents/blood , Immunosuppressive Agents/therapeutic use , Male , Mass SpectrometryABSTRACT
Drug-related illness in the United States factors substantially in health care costs, although often these illnesses and their attendant costs are preventable. One strategy for minimizing adverse drug reactions is to provide drug information to consumers in the form of prescription counseling at pharmacies. The Omnibus Budget Reconciliation Act of 1990 (OBRA 1990) contained provisions for mandating such counseling to Medicaid patients. OBRA 1990 was implemented in 1993, but most states acted quickly to extend counseling services to all patients receiving prescription drugs. We looked at the extent and quality of prescription counseling available in community pharmacies 1 decade after OBRA 1990 was written. We evaluated the counseling services afforded at large chain pharmacies, independent community pharmacies, and on-line pharmacies for a hydrochlorothiazide prescription. We found that most (69%) pharmacies offered to provide prescription counseling service, and that average counseling index scores, a measure of the quality or extent of information provided as determined by a Rasch analysis, were generally satisfactory. Our observations based on a single prescription for hydrochlorothiazide, along with other studies, suggest that there is a positive upward trend in the number of pharmacies providing prescription drug information, and that the extent of information provided suggests that the objectives of OBRA 1990 and related legislation to reduce ADRs are being fundamentally satisfied.
Subject(s)
Counseling , Medicaid/legislation & jurisprudence , Patient Education as Topic , Pharmaceutical Services/legislation & jurisprudence , Pharmaceutical Services/standards , Pharmacies/standards , Professional-Patient Relations , Antihypertensive Agents/therapeutic use , Attitude of Health Personnel , Budgets/legislation & jurisprudence , Evaluation Studies as Topic , Health Services Needs and Demand , Humans , Hydrochlorothiazide/therapeutic use , Pharmaceutical Services/economics , Pharmacies/economics , Pharmacies/statistics & numerical data , Quality Assurance, Health Care , Surveys and Questionnaires , United StatesABSTRACT
With estimates of the percentage of pharmaceuticals that are subject to metabolism by the cytochrome P-450 enzymes (CYPs) in excess of 80%, the relative activities of these enzymes in various subpopulations and even in individual patients can have important ramifications in matters ranging from dose selection to prediction of toxicity to suitability of a new chemical entity (NCE) for continued drug development. The interindividual variation in CYP activities can be profound, and the differences may be due to environmental/physiologic factors, genetic factors, or both. With regard to the process of drug development, it would be useful to know as early in the development process as possible which CYPs are likely to process a NCE, the likely interindividual variation in the processing of a NCE by CYPs, which CYP activities are likely to be altered by a NCE, and the magnitude by which CYP activity is likely to be altered by a NCE. The latter two, in particular, will be useful in predicting drug interactions between the NCE and currently available drugs. For purposes of establishing treatment regimens that are maximally effective and minimally toxic, it follows that advance knowledge of probable CYP activities could be helpful. To the extent that phenotypic expression of CYP activity corresponds to CYP genotype, it may be possible a priori to design optimized therapeutic regimens for selective CYP substrates based on knowledge of a patient's CYP genotype. Because the expression of CYP activity is determined predominantly by prevailing environmental/physiologic conditions, tailoring drug therapy to meet individual patient needs can require knowledge of a patient's CYP phenotype. Strategies for genotyping and phenotyping CYP-450 activity are discussed with special attention paid to in vivo phenotyping methods.