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1. To investigate the effect of cimetidine on the pharmacokinetics of R(−)− and S(+)-ibuprofen, six healthy male volunteers received orally 800 mg racemic ibuprofen both in the drug-free state (control phase, C) and on the second day of a 3 day course of oral cimetidine, 1 g daily (treatment phase, T). The two phases (14 days apart) were randomised in a balanced cross-over manner. 2. The plasma concentrations of R(−)− and S(+)-ibuprofen were measured by high-performance liquid chromatography (h.p.l.c.). The protein binding of the enantiomers was assessed in a selection of plasma samples from each volunteer. Following alkaline hydrolysis of glucuronide conjugates, the urinary recoveries of ibuprofen and its major metabolites were measured by h.p.l.c. 3. There was no difference (P greater than 0.05, two-tailed Student's t-test; data expressed as mean +/- s.d.) between C and T phases in the total area under the plasma concentration-time curve of R(−)−ibuprofen (C 4514 +/- 1063 mg 1(-1) min vs T 4665 +/- 1435 mg 1(-1) min) and S(+)- ibuprofen (C 6460 +/- 1063 mg 1(-1) min vs T 6886 +/- 1207 mg 1(-1) min). Similarly, for each enantiomer, there was no difference between the two phases in the terminal half-life, the maximum plasma concentration or the time of its occurrence. 4. Cimetidine treatment had no effect (P greater than 0.05) on the time-averaged percent unbound in plasma of R(−)−ibuprofen (C 0.419 +/- 0.051% vs T 0.435 +/- 0.060%) and S(+)-ibuprofen (C 0.643 +/- 0.093% vs T 0.633 +/- 0.053%). (ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

1. Although it is well recognised that the enantiomers of a chiral drug may possess different pharmacokinetic and pharmacodynamic properties, many studies dealing with chiral drugs which are administered as their racemates rely on non-stereoselective analytical techniques. 2. We present a theoretical analysis to illustrate the potential which exists for misinterpretation of drug disposition and plasma drug concentration- effect data generated for a racemic drug using a non-stereoselective assay. 3. It was shown that the use of such an analytical method can lead to the collection of data which may be both quantitatively and qualitatively inaccurate with respect to the individual enantiomers. For example, the clearance of the unresolved drug may indicate concentration- and time-dependence even though this pharmacokinetic process is concentration- and time-independent for each of the enantiomers. 4. The problems discussed emphasise the need to consider stereoselectivity in clinical pharmacological studies involving racemic drugs. [ABSTRACT FROM AUTHOR]

The effect of erythromycin on the pharmacokinetics of phenytoin was studied in eight healthy volunteers using a balanced randomised cross- over design. Volunteers received a single oral dose of 400 mg of phenytoin sodium during each phase. During the treatment phase, the phenytoin sodium dose was administered 4.5 days after the commencement of a 7 day course of erythromycin base (250 mg every 6 h). There was no significant difference between the control and treatment phases (P greater than 0.05) with respect to the area under the plasma phenytoin concentration-time curve, the fraction of phenytoin unbound in plasma, the area under the unbound phenytoin concentration-time curve, the elimination half-life of phenytoin or the fraction of the dose excreted in urine as free and conjugated hydroxyphenylphenylhydantoin. This single dose study indicated that the intrinsic clearance of unbound phenytoin was unaffected by the concurrent administration of erythromycin. [ABSTRACT FROM AUTHOR]

Objectives: Pricing polices used in many countries are often viewed in the United States as a mechanism of price constraint. Support for this contention has arisen from pricing studies which demonstrate that the United States pays higher prices for many pharmaceutical products. No study to date, however, has examined the prices paid for pharmaceuticals that provide significant health gain, which might be expected to be lower where price constraints were operating. This study aimed to examine prices paid by federal government programs and agencies in Australia and the United States for pharmaceutical products that provide significant health gain., Methods: Products identified by the US Food and Drug Administration and the Canadian Patented Medicines Prices Review Board as likely to confer significant health gains between 1999 and 2004 were identified. Australian and USfederal government prices ($US) and US average manufacturer prices (AMP), which do not include discounts or rebates, during the second quarter of 2006 were compared., Results: Of 22 products for which comparisons were possible, Australian prices were higher than the US Federal Supply Schedule (FSS) prices for 14 (64%) products. When compared with AMP, Australian prices were higher for eight of the 22 products. Overall, Australian prices were higher on average by 4.2% when compared with the FSS and lower by 14.4% when compared with the AMP., Conclusion: These results suggest that Australian prices for medicines representing significant advances in therapy are similar to those paid under key US programs despite fundamental differences in policy contexts.

Objective: To examine whether the sale of medicines via the internet supports their safe and appropriate use., Design: e-Pharmacy websites were identified using key words and a metasearch engine and the quality of information published on these websites was surveyed using the DISCERN tool. A case scenario and internet pharmacy practice standards were also used to evaluate the quality of care delivered., Setting and Participants: Between July and September 2001 104 websites were surveyed and 27 sent either Sudafed (pseudoephedrine HCl), St John's wort products, or both to a residential address in Melbourne, Australia., Main Outcome Measures: Quality of health information (DISCERN ratings), information exchanged between e-pharmacy staff and consumers, and product and delivery costs., Results: Of 104 e-pharmacies from at least 13 different countries, 63 websites provided some health information but overall the quality of the information was poor. Only three website operators provided adequate advice to consumers to avoid a potential drug interaction. The costs for a daily dose of pseudoephedrine HCl (240 mg) ranged from 0.81 Australian dollars to 3.04 Australian dollars, and delivery costs from 3.28 Australian dollars to 62.70 Australian dollars., Conclusion: Consumers who self-select medicines from websites have insufficient access to information and advice at the point of ordering and on delivery to make informed decisions about their safe and appropriate use.

Objective: E-pharmacies are web sites selling prescription-only medicines and other products including non-prescription and complementary medicines to consumers via the internet. This study aims to evaluate the quality of global e-pharmacies, discuss whether e-pharmacies support the safe and appropriate use of medicines, and consider how we can protect consumers in the future., Methods: A survey of public information published on global e-pharmacy web sites was conducted between July and September 2001. We used a meta-search engine, Copernic, and the search terms of 'online' or 'internet', and 'pharmacy', 'pharmacies' and 'medicines' to identify a sampling frame of global e-pharmacies. We surveyed all web sites in the sampling frame except those under construction or only offering electronic refills, members-only and non-English web sites. Survey data included country of origin, range of medicines sold, prescription requirements, availability of online medical consultations and pharmacists' advice, quality accreditation seals, policies and advertisements., Results: E-pharmacies operated in at least 13 countries; however, the country of origin could not be identified for 22 web sites. Twenty web sites (19%) appeared to supply prescription-only medicines with no prescription required. Only 12% of e-pharmacies displayed quality accreditation seals. We observed information published on e-pharmacy web sites that potentially undermines the safe and appropriate use of medicines., Conclusion: Safeguarding consumers and ensuring the quality of web sites that sell medicines across state and national boundaries is both complex and difficult. Strategies to improve the quality of e-pharmacies include independent third-party regulation of providers, evaluation and enforcement of sanctions in cases of dissemination of fraudulent or harmful information and practices, self-regulation and consumer education. The development of internet regulatory technologies themselves and the resolution of jurisdictional issues offer future solutions but international co-operation is vital.

Objective: To determine the proportion of South Australians accessing online health care information, predictive characteristics of online health seekers, nature of the information sought and consumer behaviour., Methods: A probability-based survey of 3,027 South Australians, aged 15 years and older, as part of the Spring 2000 South Australian Health Omnibus., Results: Internet access decreases with age, while the prevalence of online health seekers is constant (26% to 28%) among people aged between 15 and 54 years. Predictive characteristics of online health seekers include gender, age, education and income. Most commonly sought information is the cause or description of disease (60%). Consumers use online health information as a second opinion (19%), discuss it with their doctor or pharmacist (16%), or change their health care management (11%)., Conclusions: The Australian prevalence of online health seekers is likely to be slightly higher than 21%., Implications: The Intemet can deliver preventative and clinical health information to a critical mass of Australians, but poorer and older Australians may be unable to access it.

Objective: To systematically review the effect of consumer use of online health information on decision-making, attitudes, knowledge, satisfaction and health outcomes and utilization., Search Strategy: Electronic databases searched included the Cochrane Controlled Trials Register, MEDLINE, PREMEDLINE (to 14 March 2001), CINAHL, Australian Medical Index, Health and Society, National Institutes of Health Clinical Trials Database and CenterWatch., Inclusion Criteria: All post-1995 comparative studies (including controlled studies, before and after studies, and interrupted time series analyses) of Internet users vs. non-Internet users and other communications mediums, and Internet characteristics such as e-mail vs. other communication mediums, were included. Outcomes included consumer decision-making, attitudes, knowledge, satisfaction and measurable changes in health status or health utilization., Data Extraction and Synthesis: One reviewer screened all papers then two reviewers independently assessed studies against the selection criteria and any discrepancies were resolved by discussion with a third reviewer. No attempt was made to combine the data for further statistical analysis., Main Results: We identified 10 comparative studies. Studies evaluated the effectiveness of using the Internet to deliver a smoking cessation programme, cardiac and nutrition educational programmes, behavioural interventions for headache and weight loss, and pharmacy and augmentative services. All studies showed some positive effects on health outcomes, although the methodological quality of many studies was poor., Conclusions: Despite widespread consumer Internet use to obtain health-care information, there is almost a complete lack of evidence of any effects this may have on health outcomes.

While there is a global trend to switch medicines from prescription to non-prescription status, Australia has created a unique schedule of 'pharmacist only medicines' (POM). Such medicines may provide consumers with greater choice and control of health care decisions. However, the impact of these actions has not been evaluated. Public health concerns including the appropriate use of medicines, awareness and equity of access to POM, and access to information on POM are discussed using antifungal vaginal products as an example. The National Medicines Policy advocates a partnership approach to achieve improved health outcomes by the quality use of medicines, however currently no data on POM are available. Recommendations include changes to legislation, public health data collection and the provision of quality information including pharmaceutical and non-pharmaceutical interventions.

National medicinal drug policies are employed around the world as a means of maximizing the benefits of medication use. An essential component to the implementation of these policies is their concurrent evaluation, which informs future policy implementation and strategic directions. The overall effect of the policy can be measured by monitoring changes in health outcomes and hospitalization rates for conditions that can be managed with appropriate medication use have been proposed as a potential outcome indicator of national medicinal drug policies. In this paper, a method for establishing the validity of this indicator is described. The method enables suitable conditions to be identified and takes into account potential confounding factors. To demonstrate this a case study of hospitalization rates for gastrointestinal ulcer is presented. The analysis shows that hospitalization rates are suitable as outcome indicators of quality medication use where the hospitalization rate is not confounded by changes in the population profile, disease prevalence and severity, diagnosis, hospital based policies, coding practices, environmental factors or hospital based treatments, but is responsive to changes in the utilization of medication. This method could be used in many countries for determining relevant and valid indicators for monitoring health outcomes., (Copyright 1999 John Wiley & Sons, Ltd.)

Objective: To examine the extent of drug-related hospital admissions in Australia by reviewing Australian studies published between 1988 and 1996., Data Sources and Study Selection: The terms "drug-related", "admissions", "readmissions", "hospitalisation", "hospitalization" and "iatrogenic" were used to search MEDLINE and Australian Public Affairs Information Service databases. The Australian Journal of Hospital Pharmacy and conference proceedings of the Society of Hospital Pharmacists and the Australasian Pharmaceutical Science Association were searched manually. Studies were included if they were Australian, had the primary aim of identifying drug-related admissions, and had at least one clinical pharmacist or medical practitioner review the admissions., Data Extraction: Total number of admissions assessed; proportion considered drug-related; drug groups implicated; and proportion considered avoidable., Data Synthesis: 14 studies were identified; 2.4%-3.6% of all hospital admissions were reported to be drug-related. 6%-7% of emergency admissions, 12% of all admissions to medical wards and 15%-22% of all emergency admissions among the elderly were drug related. Between 32% and 69% of drug-related admissions were reported as definitely or possibly preventable. Drug groups most commonly implicated were cytotoxics, cardiovascular agents, antihypertensives, anticoagulants and non-steroidal anti-inflammatory drugs., Conclusion: Drug-related hospital admissions are a significant and expensive public health problem in Australia, and approximately half were considered possibly or probably preventable.

In the present study, the possibility that cyclophosphamide or a cyclophosphamide metabolite may be accelerating the clearance of triiodothyronine has been examined. Following administration of exogenous triiodothyronine to saline- and cyclophosphamide-treated rats, the area under the plasma concentration time curve (AUC), apparent clearance (CLapp) and half-life of triiodothyronine were measured. AUC (34.43 +/- 12.34 compared with 33.32 +/- 9.92 nmol h L-1). CLapp (36.30 +/- 12.89 compared with 37.51 +/- 11.16 mL h-1) and half-life (7.50 +/- 1.39 compared with 6.40 +/- 0.96 h) were not significantly different in the control rats compared with the cyclophosphamide-treated rats. As cyclophosphamide does not appear to alter the elimination of triiodothyronine, it is likely that cyclophosphamide or a cyclophosphamide metabolite is acting at the hypothalamo-pituitary axis, reducing the synthesis or release of thyroid stimulating hormone and consequently decreasing the levels of triiodothyronine and thyroxine.

Objective: The influence of hypoxaemia on the disposition of two common drugs has been examined in ten adults with stable chronic respiratory failure., Methods: There were two experimental periods in this cross-over study: during these periods supplemental oxygen was either withheld or administered to impose clinical hypoxaemia or maintain normoxaemia, respectively. Each participant received either oral (40 mg) or intravenous (20 mg) frusemide combined with oral paracetamol (500 mg) on consecutive days of the two experimental periods., Results: The total (bound plus unbound) plasma clearance of frusemide during hypoxaemia (arterial oxygen tension, PaO2 < or = 50 Torr) was not significantly different from the value during normoxaemia (PaO2 > or = 60 Torr) [76.9 and 62.4 ml.min-1]. The volume of distribution was not affected by acute hypoxaemia (121 ml.kg-1 without and 109 ml.kg-1 with oxygen; P > 0.05). Renal and non-renal clearances of frusemide were similar during the period of hypoxaemia (31 and 38 ml.min-1, respectively) compared to respective values during supplemental oxygen delivery (29 and 32 ml.min-1). The absolute bioavailability of frusemide during hypoxaemia (0.62) was not different to that obtained during normoxaemia (0.56). The combined sodium and potassium excretion rate (expressed as a function of the frusemide excretion rate) was not altered by changing the oxygen tension. The pharmacokinetics of paracetamol were unaffected by hypoxaemia.

Tiludronate is a bisphosphonate evaluated extensively as an osteoregulator in the treatment of metabolic bone disorders. It is highly polar and has a low and variable oral absorption similar to its related compounds. An absolute bioavailability of approximately 6% has been reported with large inter- and intra-subject variability. The extent of absorption is increased at doses above 400 mg and may be reduced by a factor of 5 when tiludronate is administered with, or within 2 h after, food or dairy products. Approximately 90% of tiludronate is bound to serum albumin, and the binding is linear in the concentration range 1-10 mg/L. Preliminary in vitro studies using human hepatocytes failed to show any evidence of biotransformation of tiludronate. The elimination half-life in patients with normal renal function is approximately 40-60 h, but is significantly increased in subjects with severe renal impairment. The renal clearance (0.7 L/h) is independent of dose and suggests that glomerular filtration is the mechanism responsible for elimination. Approximately 50% of the absorbed dose is bound to bone and the rate of release of the drug from this site is limited by bone turnover. In vitro experiments indicate that tiludronate is not an enzyme inducer or inhibitor. Drug interaction studies with the nonsteroidal agents acetylsalicylic acid, indomethacin, and diclofenac indicate that only with indomethacin was there any change in the pharmacokinetic parameters, and that these changes were minimal and unlikely to be of clinical significance. Tiludronate does not influence the pharmacokinetics of digoxin at steady state. Tiludronate appears to exhibit similar pharmacokinetic behavior to other bisphosphonates with the exception that its absolute bioavailability is significantly higher than that previously reported for clodronate and pamidronate. The impact of its pharmacokinetic properties on clinical outcome has yet to be determined.

1. Two different aspects of the effects of the cytotoxic agent cyclophosphamide (CP) on rat P450 and associated enzymes have been examined. 2. First, the effects of CP, administered as a single 200 mg/kg dose, on hepatic and pulmonary P450 and some associated enzymes in the female rat have been investigated. Second, the effects of repeat doses of CP (40 mg/kg on days 0-4 with killing on days 5, 8 and 11) to the male rat have been examined. 3. CP decreased the activity of the female rat hepatic enzymes 2A1, 2C6 and/or 2C12 and 2E1, NADPH-P450 oxidoreductase and 17 beta-oxidoreductase and the pulmonary enzyme 2B, 7 days after its administration. The decreases in the activity of the enzymes 2E1 and NADPH-P450 oxidoreductase were accompanied by a corresponding change in the amount of enzyme protein indicating that the alteration in expression of these enzymes occurred via changes in transcription and/or translation or protein degradation. 4. CP also impaired its own activation 7 days after its administration to the female rat. 5. The change in female enzyme profile was accompanied by a reduction in the hormones oestradiol, T4 and T3 7 days after CP administration. 6. Despite an apparent trend for an increase in activity on day 5, a decrease on day 8 and a subsequent increase on day 11, repeat doses of CP to the male rat generally did not alter the P450 isoforms 2A2, 2B1, 2C11, 2E1 and 3A2 or 17 beta-oxidoreductase, NADPH-P450 oxidoreductase and steroid 5 alpha-reductase. 7. Chronic administration of CP to the male rat significantly reduced erythromycin demethylase and NADPH-P450 oxidoreductase 8 days following commencement of dosing and significantly increased 2A2 11 days following commencement of dosing. There was also a statistically significant increase in pulmonary 2B 5 days following commencement of dosing. 8. Plasma testosterone and TSH were unchanged following repeated dosing with CP while T3 was significantly decreased on days 5, 8 and 11 and T4 was significantly decreased on day 8.

Many countries have established procedures for the introduction of generic pharmaceutical products. In order to protect consumers, these generic products must be demonstrated to be therapeutically equivalent to a previously approved product, typically an innovator product. The therapeutic equivalence of a generic and an innovator product is most commonly based on the demonstration of bioequivalence, i.e. clinically insignificant differences in the rate and extent of drug absorption usually assessed from pharmacokinetic measurements. This article reviews the bioequivalence requirements for generic products and, in the interest of promoting international harmonisation, highlights those areas where differences exist among countries.

A 1,179 bp and a 1,424 bp full-length aryl sulfotransferase cDNAs were isolated from a human brain cDNA library. Their coding domains are 93% identical, each encoding a cytosolic protein of 295 amino acids. Their deduced amino acid sequences of these cDNAs are also 93% identical. The 1179 bp brain cDNA has an identical coding domain to a previously reported human liver aryl sulfotransferase cDNA but it has a different 5' noncoding sequence. Northern blot analysis using a probe specific for the 1,424 bp cDNA identified a 1500 bp band in mRNA of human liver, colon, kidney and lung. In a human hepatocellular carcinoma the same band plus an extra larger band was also recognised. An intron of the gene encoding the 1424 bp cDNA was also identified.

A full-length aryl sulfotransferase cDNA was isolated from a human liver cDNA library. It was 1155 bp long containing a coding region of 885 basepairs encoding a cytosolic protein (M(r) 34178 Da) of 295 amino acids. This human cDNA shared 80% homology to the rat aryl sulfotransferase cDNA, 58% to the bovine and rat oestrogen sulfotransferase cDNAs, 53% to the rat hydroxysteroid sulfotransferase cDNA and 51% to the human liver dehydroepiandrosterone sulfotransferase cDNA over its whole 885 bp coding region. The deduced amino acid sequence of this human cDNA was 79% homologous to that of the rat aryl sulfotransferase cDNA and the putative common-substrate binding site motif GXXGXXK of the sulfotransferases has been conserved in this human amino acid sequence. At least two sizes of this human aryl sulfotransferase mRNA were detected in the human liver and lung.

A cDNA encoding an isoenzyme of rat liver aryl sulphotransferase was isolated from a rat liver bacteriophage Lambda gt 11 library by the polymerase chain reaction technique. The resulting cDNA was functionally expressed in COS-7 cells and characterised by determining the sulphating capacity of the cells with a range of substrates. The COS-expressed enzyme catalysed the sulphation of both phenol and dopamine with Kms of the same order as those obtained for the high affinity isozyme in rat liver cytosol, while low activity was observed with tyrosine methyl ester. The common food additive vanillin was also a good substrate for sulphate conjugation. The sulphation of vanillin catalysed by the COS-expressed enzyme was consistent with a single enzyme system, in contrast, the kinetics of the reaction catalysed by cytosolic sulphotransferase indicated that vanillin was sulphated by more than one isozyme.

1. The disposition of phenytoin and tolbutamide was compared in eighteen healthy young adults separately administered single therapeutic doses (sodium phenytoin 300 mg, tolbutamide 500 mg) of the two drugs. 2. Within the group, ratios of ranges of total and unbound areas under the plasma concentration-time curves were similar for both drugs. 3. There were significant (P < 0.001) correlations between total (r = 0.88) and unbound (r = 0.86) areas under the plasma phenytoin and tolbutamide concentration-time curves. 4. The results are consistent with the involvement of the same cytochrome P-450 isoenzyme(s) in the metabolism of tolbutamide and phenytoin.

The inhibition of steroid 6 beta-hydroxylase activity by anhydroerythromycin, an acid breakdown product of erythromycin, has been studied and compared to the effects of erythromycin using liver microsomes from control and dexamethasone pretreated rats and human liver microsomes. Both anhydroerythromycin and erythromycin were found to be demethylated, thus both fulfil the prerequisites for possible metabolite-cytochrome P450 complex information. The formation of a metabolite-cytochrome P450 complex was demonstrated for anhydroerythromycin by preincubating NADPH fortified microsomes with anhydroerythromycin. This complex formation could be reversed by incubating the microsomes in 50 microM potassium ferricyanide. Anhydroerythromycin was a more potent inhibitor of androst-4-ene-3,17-dione (androstenedione) 6 beta-hydroxylation than erythromycin. Kinetic analysis shows that there are probably two cytochromes P450 involved in androstenedione 6 beta-hydroxylation in control rat microsomes both of which are inhibited by anhydroerythromycin. There are at least two forms of cytochrome P450 responsible for androstenedione 6 beta-hydroxylation in microsomes from dexamethasone pretreated rats but only the high affinity form is inhibited by anhydroerythromycin. "Atypical" kinetics were observed in human microsomes but inhibition of androstenedione 6 beta-hydroxylation was observed with 5 microM anhydroerythromycin at all androstenedione concentrations used. Inconsistencies have been observed in the literature with respect to clinical interactions observed with erythromycin. Since anhydroerythromycin appears to be a more potent inhibitor of androstenedione 6 beta-hydroxylation than erythromycin, we speculate that the variable blood levels of anhydroerythromycin found after dosing with erythromycin may explain these discrepancies.

The relevance of EEG effect parameters as a measure of pharmacological effect intensity of benzodiazepines was evaluated. The concentration-EEG effect relationships of four benzodiazepine agonists, flunitrazepam, midazolam, oxazepam and clobazam, were quantified in individual rats and correlated with receptor affinity and anticonvulsant effect intensity of these compounds. Male Wistar-derived rats received a single i.v. dose of flunitrazepam (2.5 mg/kg), midazolam (5 mg/kg), oxazepam (10 mg/kg) and clobazam (20 mg/kg). Arterial blood samples were drawn frequently and EEG was monitored continuously until it had returned to preadministration levels. The concentrations of the benzodiazepines were determined by chromatographic means. Plasma protein binding was determined at 37 degrees C by ultrafiltration. The amplitudes in the 11.5 to 30 Hz frequency range, determined by aperiodic analysis, was used as EEG effect measure. Concentration-EEG effect relationships were derived by a pharmacokinetic-pharmacodynamic modeling procedure and characterized by the sigmoidal Emax model. The EC50 based on free drug concentrations (EC50,U, mean +/- S.E.) calculated for flunitrazepam (4.2 +/- 0.7 ng/ml) and midazolam (3.7 +/- 0.5 ng/ml) were similar and significantly less than the values for oxazepam (49 +/- 4 ng/ml) and clobazam (277 +/- 34 ng/ml) and illustrates the importance of using parameters referenced to unbound drug for comparative purposes. The maximal responses (Emax) for midazolam, oxazepam and clobazam were significantly less than for flunitrazepam suggesting that these three drugs may be regarded as partial agonists when compared to flunitrazepam. Receptor affinity was determined based on displacement of [3H] flumazenil in a washed brain homogenate at 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Ibuprofen is a chiral drug which is used clinically as a racemate. The pharmacological properties of ibuprofen reside almost exclusively with the S(+)-enantiomer. However, a portion of R(-)-ibuprofen is metabolically inverted to its pharmacologically active, mirror-image form. To investigate the influence of increasing dose of racemic ibuprofen on the pharmacokinetics of its individual enantiomers, four healthy male volunteers were given racemic ibuprofen (200, 400, 800, and 1200 mg), orally, on four occasions. The study was conducted using a balanced cross-over design. The extent of absorption of ibuprofen, as assessed by the total urinary recovery of ibuprofen and its metabolites, was extensive and independent of the administered dose. At all four doses, the area under the total and unbound plasma concentration-time curves (AUC and AUCu, respectively), and the unbound fraction in plasma, were significantly greater for the S(+)-enantiomer. With increasing ibuprofen dose, there was a less than proportional increase in the AUC of each enantiomer, while the AUCu for both enantiomers increased in direct proportion to the administered dose. The time-averaged unbound fraction of each enantiomer increased significantly with increasing dose, which caused the non-linearity between AUC and dose. It was predicted that the metabolic intrinsic clearance of each enantiomer, and the fraction of R(-)-ibuprofen which was metabolically inverted to S(+)-ibuprofen, was independent of the administered dose.

Eighteen healthy, non-smoking, adult volunteers participated in single and multiple dose three-way crossover studies to evaluate a sustained-release, pellet-filled capsule of theophylline, Austyn. The effect of food on the bioavailability of the sustained-release capsule was investigated by administering 300 mg single doses of Austyn, with a high-fat meal and without food and a divided 300 mg dose of the reference product Elixophyllin elixir, given after fasting. Plasma theophylline concentrations were measured by fluorescence polarization immunoassay (FPIA) which had been validated against HPLC. The single dose study data showed that there were no significant differences (n = 18, ANOVA, p greater than 0.05) between the three regimens with respect to AUC0-infinity values (mg h l-1), (mean +/- SD); Elixophyllin fasting = 97.1 +/- 33.7, Austyn with food = 90.9 +/- 31.3, Austyn fasting = 91.2 +/- 33.8. Similarly, multiple dosing with rapid-release Nuelin tablets, Austyn capsules, and sustained-release Theo-Dur tablets demonstrated that there were no significant differences between regimens with respect to AUC0-24h, AUC0-12h, and AUC12-24h values calculated from the steady-state concentrations (5th day, 24 h sampling). However, the percentage fluctuation at steady-state over the total blood sampling period was significantly less for treatment with the sustained-release capsule. Austyn, compared with the sustained-release tablet, Theo-Dur (Austyn = 36.7 +/- 13.7 per cent, Theo-Dur = 53.1 +/- 14.1 per cent). The results of the single and multiple dose studies indicate that Austyn capsules demonstrate complete bioavailability, and good controlled release characteristics not influenced by concomitant intake of a high-fat meal and with no evidence of dose dumping.

The ability of rabbit liver microsomes to 4-hydroxylate phenytoin to 5-(4-hydroxyphenyl)-5-phenylhydantoin was studied. No significant difference was observed between the capacity of control and rifampicin, phenobarbital, acetone, 2,3,7,8-tetrachlorodibenzo-p-dioxin and phenytoin induced rabbit liver microsomes to 4-hydroxylate phenytoin. In reconstitution experiments using six purified rabbit cytochromes P450 isozymes, only P450IIC3 was capable of 4-hydroxylating phenytoin whereas P450IA1, P450IA2, P450IIB4, P450IIIA6, and P450IVB1 were inactive. Further, anti-P450IIC3 IgG completely inhibited phenytoin 4-hydroxylase activity in rabbit liver microsomes. The above data suggest a major role for the constitutive isozyme P450IIC3 in phenytoin 4-hydroxylase activity in rabbit liver. In human liver microsomes P450IIC3 IgG inhibited phenytoin 4-hydroxylase activity by 66%, suggesting that an ortholog to rabbit P450IIC3 is in part responsible for this activity in man.

Thirteen male patients were administered 20 mg of temazepam orally 1 to 2 h prior to undergoing spinal anaesthesia for a urological procedure. Samples of blood and CSF were drawn just before insertion of the spinal and the concentration of drug estimated in these two media. The results obtained indicated that a highly significant correlation existed between the unbound concentration of temazepam in plasma and the concentration of drug present in CSF. Temazepam appeared to be an effective light pre-medicant in all of the subjects studied.

Moxalactam kinetics during continuous ambulatory peritoneal dialysis (CAPD) was followed in eight patients after a single intraperitoneal dose of 1 g. Approximately 60% of the dose was absorbed after a dwell time of 4 h. Dialysis solutions were exchanged at 4-h intervals with an overnight dwell of 8 h. The mean (+/- standard deviation) elimination half-life was 13.2 +/- 2.9 h, and the mean apparent volume of distribution was 0.22 +/- 0.08 liters/kg. Mean total clearance was 11.5 +/- 2.4 ml/min, with a mean dialysis clearance of 2.3 +/- 0.5 ml/min. The maximum concentration in plasma ranged from 24.5 to 54.1 micrograms/ml. Moxalactam concentrations in the peritoneal dialysis fluid were above 80 micrograms/ml during the first exchange and above 2 micrograms/ml for a further three exchanges. A suggested intraperitoneal dose regimen for patients undergoing CAPD is 1 g initially, followed by 15 to 25% of the recommended dose for normal patients given at the same time intervals, or 30 to 50% of the recommended dose at twice the usual intervals. Moxalactam is suggested for initial treatment of peritonitis in CAPD patients who do not have ready access to the antibiotic of choice.

The effect of valproate on the pharmacokinetics of phenytoin after a single i.v. injection is described in this study. Valproate is shown to significantly increase the total clearance, i.e., 23.8 to 30.4 ml . min-1 . kg-1 and volume of distribution, i.e., 0.92 to 1.25 liter . kg-1. No significant change was shown for the half-life of phenytoin. The pharmacokinetic parameters calculated for unbound phenytoin showed no significant differences between those rats infused with phenytoin or phenytoin-valproate. Significantly higher concentrations of 5-(p-Hydroxyphenyl)-5-phenylhydantoin (HPPH) were observed in those rats given an i.v. injection of phenytoin-valproate. In vitro studies with rat liver microsomes demonstrated that valproate inhibits the metabolism of HPPH to its glucuronide. This was further exemplified when significant differences were observed in the clearance and volume of distribution of HPPH in rats given an i.v. injection of HPPH or HPPH plus valproate. The results of this study demonstrate that in the rat valproate displaces phenytoin from serum proteins and that this interaction accounts for the increased volume of distribution and clearance of total phenytoin when valproate is coadministered. However, this displacement had no effect on the pharmacokinetics of free (unbound) phenytoin. Valproate is shown to be an inhibitor of the glucuronidation of HPPH which may explain the significantly increased concentrations of HPPH observed in the rats administered phenytoin-valproate.

A cross-over study was conducted to compare the plasma phenytoin levels produced by different phenytoin preparations available in Australia. The preparations were found not to be equivalent, a liquid suspension product producing higher levels compared with capsule and tablet formulations. The clinical significance and possible explantation are discussed.

Eight healthy, male subjects participated in a balanced randomized crossover study to investigate the effect of a course of co-trimoxazole (CT; combination of sulphamethoxazole 800 mg and trimethoprim 160 mg, twice daily for 5 days) on the pharmacokinetics and urinary metabolite profile of an orally administered dose of theophylline (TH). There were no significant differences (p greater than 0.05) between the control and treatment phases with respect to any of the following pharmacokinetic parameters of TH: area under the plasma total TH concentration time curve; fraction unbound in plasma; area under the plasma unbound TH concentration time curve; terminal half-life; apparent volume of distribution; apparent total plasma clearance and renal clearance. The urinary recoveries of 1-methyluric acid, 1.3-dimethyluric acid and of theophylline were not significantly different (p greater than 0.05) between the two study phases. There was a significant difference (p less than 0.05), however, in the urinary recovery of 3-methylxanthine (11.3 +/- 2.6 per cent TH alone versus 13.9 +/- 3.6 per cent TH-CT) and in the total urinary recovery of TH and its metabolites (76.5 +/- 8.2 per cent versus 85.3 +/- 7.0 per cent), the latter finding suggesting that CT may have caused a small increase in the extent of TH absorption. The results of the study indicated that CT did not inhibit the biotransformation of TH.

Displacement of phenytoin from plasma proteins by valproate causes a reduction in total serum phenytoin levels. However, no adjustment of phenytoin dosage is warranted, unless clinically indicated, since the free phenytoin levels remain unchanged.

In children, the blood level of phenytoin was found to be significantly higher when 100 mg capsules rather than 100 mg tablets were administered. When, on the other hand, 30 mg capsules and tablets were compared; the situation was reversed; tablets produced significantly higher blood levels of phenytoin than did the capsules. The significance and possible explantation of these findings are discussed.

We have developed a novel and reproducible method for determining the plasma protein binding of the two ibuprofen enantiomers in the presence of each other. The method involves the use of radiolabelled racemic ibuprofen, equilibrium dialysis, derivatization of the enantiomers to diastereomeric amides, high-performance liquid chromatography, and radiochemical analysis. We have determined the plasma protein binding of R(-)- and S(+)-ibuprofen in 6 healthy male volunteers after the oral administration of 800 mg racemic ibuprofen. The mean time-averaged percentage unbound of the R(-)-enantiomer, 0.419 was significantly less than that of the S(+)-enantiomer, 0.643, consistent with stereoselective plasma protein binding. The percentage unbound of each ibuprofen enantiomer was concentration-dependent over the therapeutic concentration range and was influenced by the presence of its optical antipode.

The bioavailability of a rapidly dissolving tablet of theophylline and three brands of standard aminophylline tablets was estimated in a four way cross-over study involving 8 healthy adult volunteers. The relative extent of bioavailability as assessed by the measurement of the total area under the plasma concentration time curves showed no difference between the products (P greater than 0.05). Computed estimates of the rate of drug absorption were similar for all 4 products tested. The results indicate that the rapidly dissolving tablet offers no advantage in respect to rate and extent of absorption over conventional aminophylline tablets.

The pharmacokinetics of a new 10 mg sublingual tablet formulation of temazepam and those of a currently marketed 10 mg oral capsule formulation were evaluated in a group of ten healthy volunteers. No significant differences were observed between the two formulations with respect to any of the pharmacokinetic parameters assessed. Lethargy and somnolence were reported on both capsule and tablet by several subjects at a time which corresponded with the maximum concentration of drug in plasma. The data indicate that the sublingual tablet and orally administered capsule have a similar pharmacokinetic and pharmacodynamic profile.

The pharmacokinetics of theophylline following a single intravenous dose of aminophylline were determined in 8 asthmatic patients in each of the acute, the recovery and the remission phase. The overall results for mean plasma theophylline clearance (78.6 +/- 33.3 ml/kg/h), plasma theophylline half-life (4.14 +/- 1.36 h) and apparent volume of distribution (0.41 +/- 0.066 l/kg) are in accordance with previously published values. There was no general statistically significant difference in any of the pharmacokinetic parameters when results from the acute and remission phases were compared. However, certain patients showed reductions in plasma theophylline clearance in the acute phase of the illness such that a dosage regimen standardised during remission may cause toxicity if continued in the acute episode. It is suggested that monitoring the plasma theophylline levels is desirable in all patients in the acute episode.

The inadequacy of single, simple arithmetic corrections for salicylate interference in the widely employed Glynn and Kendal technique for plasma paracetamol assay is highlighted by reference to an actual case of combined salicylate/paracetamol intoxication in an infant. Attention is drawn for the first time to the not insubstantial contribution to such interference made by even the minor metabolites of salicylate. The conclusion is reached that is necessary, particularly in the assessment of paracetamol toxicity, to determine the presence of salicylate, and when present, to employ a specific method for the estimation of paracetamol.

We have studied the pharmacokinetics of the anti-mycotic ketoconazole in seven patients who took it for 1-6 months at a dose of 200 mg daily. The mean elimination half-life of the drug was 3.3 h, and although the ketoconazole was given only once daily, a satisfactory clinical response was obtained in all seven individuals. Only a small fraction of the absorbed drug (mean 0.22%) was excreted unchanged in the urine, suggesting almost complete metabolism. Our results support the concept that anti-mycotic activity in the tissues continues after the plasma drug concentration has fallen below a critical level. Our results also support the concept of a change in pharmacokinetics with chronic dosing.