A comparison of alcohol and drug disorders: is there evidence for a developmental sequence of drug abuse?

Whereas the model of Jellinek [Q. J. Stud. Alcohol 7 (1952) 673] of a predictable progression of alcoholism is generally supported, there have been few published studies regarding the natural history of illicit drug disorders. Identification of the development of drug abuse and/or dependence can inform clinicians and researchers on issues, such as diagnosis, prognosis, assessment, and prevention. This study employed a new measure adapted from the 46 events described in Jellinek's progression of alcoholism. Nine licit and illicit substances were also included within the cardsort. Fifty-two individuals motivated to enter drug treatment by a loved one were assessed pretreatment. The drug initiation sequence reported by this sample was as follows: alcohol, tobacco, inhalants, marijuana, and then other drugs. Spearman rank correlation coefficients were conducted between the drug sample and that of Jellinek yielding a modest correlation (r=.35, P=.019). These results suggest that Jellinek's model of progression of alcoholism may also apply to the development of drug disorders. However, important differences found between the alcohol and drug progressions are discussed.     

Do CYP3A and ABCB1 genotypes influence the plasma concentration and clinical outcome of donepezil treatment?

Purpose  

The aim of our study was to evaluate the impact of CYP3A4, CYP3A5, and ABCB1 polymorphisms on donepezil disposition and clinical outcome.     

Does pharmacogenetics have the potential to allow the individualisation of immunosuppressive drug dosing in organ transplantation?

The immunosuppressive drugs used in organ transplantation have a narrow therapeutic index, with rejection occurring as a consequence of underdosing and infection, malignancy and a number of drug-specific side effects with excessive dosing. Significant heterogeneity in the dose of drug required to achieve therapeutic blood concentrations adds to the complexity of the problem, which has been partly resolved by therapeutic drug monitoring. Single nucleotide polymorphisms have been identified in genes encoding metabolic enzymes, drug efflux pumps and drug targets for most of the drugs in widespread use. A pharmacogenetic approach to immunosuppressive drug prescribing remains to be tested. Based on current evidence, the most promising strategy would be use of the cytochrome P450 3A5 expressor genotype to guide initial dosing with tacrolimus.     

Development of an ADME and drug–drug interactions knowledge database for the acceleration of drug discovery and development

It is widely recognised that predicting or determining the absorption, distribution, metabolism and excretion (ADME) properties of a compound as early as possible in the drug discovery process helps to prevent costly late-stage failures. Although in recent years high-throughput in vitro absorption distribution metabolism excretion toxicity (ADMET) screens have been implemented, more efficient in silico filters are still highly needed to predict and model the most relevant metabolic and pharmacokinetic end points, and thereby accelerate drug discovery and development. The usefulness of the data generated and published for the chemist, biologist or project manager who ultimately wants to understand and optimise the ADME properties of lead compounds cannot be argued with. Collecting and comparing data is an overwhelming task for the time-pressed scientist. Aureus Pharma provides a uniquely specialised solution for knowledge generation in drug discovery. AurSCOPE^® ADME/DDI (drug–drug interaction) is a fully annotated, structured knowledge database containing all the pertinent biological and chemical information on the metabolic properties of drugs. This Aureus knowledge database has proven to be highly useful in designing predictive models and identifying potential drug–drug interactions.     

A critical evaluation of clinical decision support for the detection of drug–drug interactions

Introduction: Incorporation of clinical decision support systems (CDSSs) into computerized physician order entry assists prescribers with medication dosing, identification of duplicate therapies, drug-allergy alerts and drug–drug interactions (DDIs). The generation of DDI alerts is one aspect of CDSS that may improve patient safety and reduce adverse drug events.

Areas covered: Currents issues with the generation of DDI alerts, such as alert fatigue, unclear clinical significance and database inconsistencies are a few of the problems that have been identified with DDI alerting. Research has shown that DDI alerting may be improved through the tiering of alerts, generation of patient-specific alert and directing some alerts to clinicians other than physicians. More research in this area, such as how to decrease the variability of database rating systems, improve the identification of clinically significant alerts and increase the patient specificity of the generated DDI alerts, should be conducted.

Expert opinion: DDI knowledgebases need to take into account more patient-specific information. Strategies to avoid alert fatigue, such as DDI tiering and reducing signal:noise ratios, are important areas for future study. End-user participation and clinician feedback should be incorporated in the development of DDI knowledgebases to increase alert compliance.     

Pharmacokinetics and pharmacogenetics of anti-tubercular drugs: a tool for treatment optimization?

Introduction: WHO global strategy is to end tuberculosis epidemic by 2035. Pharmacokinetic and pharmacogenetic studies are increasingly performed and might confirm their potential role in optimizing treatment outcome in specific settings and populations. Insufficient drug exposure seems to be a relevant factor in tuberculosis outcome and for the risk of phenotypic resistance.

Areas covered: This review discusses available pharmacokinetic and pharmacogenetic data of first and second-line antitubercular agents in relation to efficacy and toxicity. Pharmacodynamic implications of optimized drugs and new options regimens are reviewed. Moreover a specific session describes innovative investigations on drug penetration.

Expert opinion: The optimal use of available antitubercular drugs is paramount for tuberculosis control and eradication. Whilst trials are still on-going, higher rifampicin doses should be reserved to treatment for tubercular meningitis. Therapeutic Drug Monitoring with limiting sampling strategies is advised in patients at risk of failure or with slow treatment response. Further studies are needed in order to provide definitive recommendations of pharmacogenetic-based individualization: however lower isoniazid doses in NAT2 slow acetylators and higher rifampicin doses in individuals with SLCO1B1 loss of function genes are promising strategies. Finally in order to inform tailored strategies we need more data on tissue drug penetration and pharmacological modelling.     

ATP binding cassette transporter A1 (ABCA1) associated proteins: potential drug targets in the metabolic syndrome and atherosclerotic disease?

The metabolic syndrome is defined as a cluster of disorders including visceral obesity, insulin resistance, hypertension, hypertriglyceridemia and low HDL. Patients have an increased risk to develop atherosclerotic disease characterized by excessive macrophage cholesterol deposition in the vascular wall. HDL removes excess cellular cholesterol which is subsequently transported to the liver for biliary excretion and thereby preserves cholesterol homeostasis. Circulating HDL levels are maintained by hepatic ATP-binding cassette transporter A1 (ABCA1) which also transports peripheral cell cholesterol to extracellular lipid acceptors. Lipid export activity of ABCA1 improves pancreatic -cell function and ameliorates insulin release. ABCA1 affects plasma membrane cholesterol distribution and formation of lipid rafts representing signalling platforms for diverse receptors including toll-like receptor 4 (TLR4). Pharmacological activation of ABCA1 pathways presumably progresses metabolic diseases, and current approaches demonstrate beneficial effects of small peptides mimicking ABCA1 ligands which stabilize ABCA1 and enhance lipid efflux similar to its physiological acceptor apolipoprotein A-I. Research of the last decade has resulted in the identification of several ABCA1 binding proteins influencing ABCA1 signalling, stability and activity. In the current review the proteins suggested to form a complex with ABCA1 are summarized and their up to now characterized features towards ABCA1 functions are described.     

Method for predicting the risk of drug–drug interactions involving inhibition of intestinal CYP3A4 and P-glycoprotein

1. To develop a method to predict the risk of drug–drug interactions involving the inhibition of intestinal CYP3A4 or P-glycoprotein, data from clinical drug–drug interaction studies of CYP3A4 and/or P-glycoprotein substrates were analysed. The ratio of inhibitor dose (Dose_i) to inhibition constant (K_i), termed the drug-interaction number, was used to index intestinal drug–drug interaction.

2. From the analysis, it was found that (1) CYP3A4 inhibitors with a drug-interaction number below 2.8?L have a low risk of interacting with substrates which exhibit intestinal first-pass metabolism and those with a drug-interaction number above 9.4?L have a high risk; (2) P-glycoprotein inhibitors with a drug-interaction number below 10.8?L have a low risk of interacting with P-glycoprotein substrates and those with a drug-interaction number above 27.9?L have a high risk; and (3) the drug-interaction number indexes, 2.8?L and 9.4?L for CYP3A4 and 10.8?L and 27.9?L for P-glycoprotein were validated by data from dual CYP3A4/P-glycoprotein substrates.

3. In conclusion, the drug-interaction number is useful for classifying the risk of drug–drug interactions involving the inhibition of intestinal CYP3A4 and P-glycoprotein. This drug-interaction number-based approach is similar to the method that the US Food and Drug Administration (USFDA) recently proposed in the draft guidance for predicting P-glycoprotein-mediated drug–drug interaction.

     

Can pharmacists influence drug prescribing? A look at eight of the top 25 drug products for 1976

The most frequently prescribed drug products were reviewed for insights into prescribing and dispensing patterns for ambulatory patients. The indications for eight of the "top" drug products were considered to be pharmacologically or therapeutically questionable. The drug products were: tetracycline, systemic; Dimetapp; Empirin Compound with Codeine; Actified; Darvon Compound 65; Darvocet-N; Donnatal; and Keflex. Drug prescribing review and prescriber education are crucially needed, as well as formulary controls when feasible.     

Role for protein kinase C delta in the functional activity of human UGT1A6: implications for drug–drug interactions between PKC inhibitors and UGT1A6

1. Many UDP-glucuronosyltransferases (UGTs) require phosphorylation by protein kinase C (PKC) for glucuronidation activity. Inhibition of UGT phosphorylation by PKC inhibitor drugs may represent a novel mechanism for drug–drug interactions.

2. The potential for PKC-mediated inhibition of human UGT1A6, an isoform involved in the glucuronidation of drugs such as acetaminophen (paracetamol) and endogenous substrates including serotonin, was evaluated using various cell model systems.

3. Of ten different PKC inhibitors screened for their effects on acetaminophen glucuronidation by human LS180 colon cells, only rottlerin (PKC δ selective inhibitor; IC₅₀?=?9.0?±?1.2 μM) and the non-selective PKC inhibitors (calphostin-C, curcumin and hypericin) decreased glucuronidation by more than 50%.

4. Using UGT1A6-infected Sf9 insect cells, calphostin-C and hypericin showed three times more potent inhibition of serotonin glucuronidation in treated whole cells versus cell lysates. However, both curcumin and rottlerin showed significant direct inhibition and so (indirect) PKC effects could not be differentiated in this model system.

5. Of nine PKC isoforms co-expressed with UGT1A6 in human embryonic kidney 293T cells only PKC δ increased protein-normalized UGT1A6-mediated serotonin glucuronidation significantly (by 63% ± 4%).

6. These results identify an important role for PKC δ in UGT1A6-mediated glucuronidation and suggest that PKC δ inhibitors could interfere with glucuronidation of UGT1A6 substrates.

     

Validation of cell-based OATP1B1 assays to assess drug transport and the potential for drug–drug interaction to support regulatory submissions

1. Transporters are carrier proteins that may influence pharmacokinetic, pharmacodynamic, and toxicological characteristics of drugs. The development of validated in vitro transporter models is imperative to support regulatory submissions of drug candidates. This study is focused on utilizing human embryonic kidney (HEK) 293 cell cultures genetically transfected with the human organic anion transporting polypeptides (OATP) 1B1 transporter to identify substrates and inhibitors in drug development.

2. The kinetics of OATP1B1-mediated uptake of [³H]-oestradiol 17β-glucuronide and inhibition of uptake by rifamycin SV were used to determine K_m, V_max, and IC₅₀ values over a range of passage numbers to investigate accuracy and precision. The mean K_m and V_max values were found to be 6.3?±?1.2 μM and 460?±?96 pmol min^?1 mg^?1, respectively. The mean IC₅₀ value for rifamycin SV was 0.23?±?0.07 μM on uptake of 1 μM [³H]-oestradiol 17β-glucuronide. These data were similar to previously reported values (accuracy greater than 82%), reproducible (precision less than 29%) and exhibited low standard deviations (SDs) obviating the need to study test compounds on more than one occasion.

3. [³H]-oestrone 3-sulfate and [³H]-pravastatin exhibited concentration-dependent OATP1B1 uptake, and statistically significant differences were observed at each concentration between uptake rates of HEK293-OATP1B1 and HEK293-MOCK cells (uptake ratios greater than or equal to 3). Propranolol showed no positive uptake ratio. Bezafibrate and gemfibrozil exhibited concentration-dependent inhibition of OATP1B1-mediated uptake of [³H]-oestradiol 17β-glucuronide with mean IC₅₀ values of 16 and 27 μM, respectively.

4. Based on the validation results, acceptance criteria to identify a test compound as a substrate and/or inhibitor using these specific cell lines were determined. These validated OATP1B1 assays were robust, reproducible, and suitable for routine in vitro evaluation of candidate drugs.