Surfing, self-medicating and safety: buying non-prescription and complementary medicines via the internet.

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.

'Pharmacist only' medicines.

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.

Hospitalization rates as outcome indicators of national medicinal drug policies: the example of gastrointestinal ulcer.

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.

Drug-related hospital admissions: a review of Australian studies published 1988-1996.

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.

The effects of cyclophosphamide on the pharmacokinetics of triiodothyronine in the male rat.

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.

The effect of hypoxaemia on drug disposition in chronic respiratory failure.

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.

Human pharmacokinetics of tiludronate.

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.

Cyclophosphamide administered repeatedly to the male rat and as a single dose to the female rat. Its effects on hepatic and pulmonary P450 and associated enzymes.

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.

Bioequivalence requirements for generic products.

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.

The influence of renal function on the enantioselective pharmacokinetics and pharmacodynamics of ketoprofen in patients with rheumatoid arthritis.

1. Single oral doses of 100 mg racemic ketoprofen were given to 15 patients (age range: 51-79 years) with rheumatoid arthritis and a range of creatinine clearances (CLCR) from 26 to 159 ml min-1. 2. The fractions unbound of (R)- and (S)-ketoprofen in plasma were determined for each subject after in vitro addition of rac-ketoprofen (enantiomer range: 1.00-6.00 micrograms ml-1) to pre-dose plasma. 3. An index of the antiplatelet effect of ketoprofen in vitro was measured as inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood (pre-dose) spiked with rac-ketoprofen. 4. In vivo studies revealed significant associations (P < 0.05) between the reciprocal of AUC for both unbound and total (bound plus unbound) (S)-ketoprofen and CLCR. Corresponding relationships were also observed for the (R)-enantiomer of ketoprofen. In addition, the half-life of each enantiomer was negatively correlated with CLCR. There was a positive relationship between the 24 h urinary recovery of combined non-conjugated and conjugated (R)-ketoprofen and CLCR while that for the (S)-stereoisomer failed to reach statistical significance (P > 0.05). 5. There was no difference between AUC for (R)- and (S)-ketoprofen for either unbound or total drug. 6. The mean +/- s.d. percentage unbound of (S)-ketoprofen in plasma (0.801 +/- 0.194%) exceeded (P < 0.05) the corresponding value for its optical antipode (0.724 +/- 0.149%). The percentage unbound of the (S)-enantiomer was higher at 6.00 micrograms ml-1 than that at enantiomer concentrations of 3.50 micrograms ml-1 and below, where it was invariant. The percentage unbound of (R)-ketoprofen was independent of plasma concentration up to 6.00 micrograms ml-1. There were no correlations between the percentage unbound of each enantiomer and either serum albumin concentration or CLCR. 7. The relationship between the serum concentration of unbound (S)-ketoprofen and the percentage inhibition of platelet TXB2 generation was described by a sigmoidal Emax equation for each patient. There was no correlation between the unbound concentration of (S)-ketoprofen in serum required to inhibit platelet TXB2 generation by 50% (EC50) and CLCR. The mean +/- s.d. EC50 was 0.216 +/- 0.143 ng ml-1. 8. These data indicate that diminished renal function is associated with an increased exposure to unbound (S)-ketoprofen, presumably due to regeneration of parent aglycone arising from the hydrolysis of accumulated acyl-glucuronide conjugates. The apparent sensitivity of platelet cyclo-oxygenase to the inhibitory effect of (S)-ketoprofen was not influenced by renal function.

Identification of two human brain aryl sulfotransferase cDNAs.

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.

Molecular characterisation of a human aryl sulfotransferase cDNA.

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.

cDNA expression studies of rat liver aryl sulphotransferase.

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.

Co-regulation of phenytoin and tolbutamide metabolism in humans.

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 drug oxidation by anhydroerythromycin, an acid degradation product of erythromycin.

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.

Pharmacokinetic-pharmacodynamic modeling of the electroencephalographic effects of benzodiazepines. Correlation with receptor binding and anticonvulsant activity.

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)

Relationship between phenytoin and tolbutamide hydroxylations in human liver microsomes.

1. The metabolic interaction of phenytoin and tolbutamide in human liver microsomes was investigated. 2. Phenytoin 4-hydroxylation (mean Km 29.6 microM, n = 3) was competitively inhibited by tolbutamide (mean Ki 106.2 microM, n = 3) and tolbutamide methylhydroxylation (mean Km 85.6 microM, n = 3) was competitively inhibited by phenytoin (mean Ki 22.6 microM, n = 3). 3. A significant correlation was obtained between phenytoin and tolbutamide hydroxylations in microsomes from 18 human livers (rs = 0.82, P less than 0.001). 4. Sulphaphenazole was a potent inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values of 0.4 microM and 0.6 microM, respectively. 5. Mephenytoin was a poor inhibitor of both phenytoin and tolbutamide hydroxylations with IC50 values greater than 400 microM for both reactions. 6. Anti-rabbit P450IIC3 IgG inhibited both phenytoin and tolbutamide hydroxylations in human liver microsomes by 62 and 68%, respectively. 7. These in vitro studies are consistent with phenytoin 4-hydroxylation and tolbutamide methylhydroxylation being catalysed by the same cytochrome P450 isozyme(s) in human liver microsomes.

Effect of racemic ibuprofen dose on the magnitude and duration of platelet cyclo-oxygenase inhibition: relationship between inhibition of thromboxane production and the plasma unbound concentration of S(+)-ibuprofen.

1. Four healthy male subjects received racemic ibuprofen (200, 400, 800 and 1200 mg), orally, on four occasions, 2 weeks apart, according to a four-way Latin-square design, in order to investigate the influence of increasing dose of ibuprofen on the magnitude and duration of its antiplatelet effect as well as on the relationship between such effect and drug concentration. 2. The antiplatelet effect of ibuprofen was assessed by measuring the inhibition of platelet thromboxane B2 (TXB2) generation during the controlled clotting of whole blood. The plasma unbound concentration of S(+)-ibuprofen, the enantiomer shown in an in vitro study to be responsible for the inhibitory effect of platelet TXB2 generation, was measured using an enantioselective method. 3. The maximum percentage inhibition of TXB2 generation increased significantly with dose from a mean +/- s.d. of 93.4 +/- 1.2% after the 200 mg dose to 98.8 +/- 0.3% after the 1200 mg dose, and there was an increase with dose in the duration of inhibition of TXB2 generation. The effect of ibuprofen on platelet TXB2 generation was transient and mirrored the time-course of unbound S(+)-ibuprofen in plasma; on all but one of the 16 occasions, serum TXB2 concentrations returned to at least within 10% of the pretreatment concentrations within 24 h of ibuprofen administration. 4. For each subject, the relationship between the percentage inhibition of TXB2 generation and the unbound concentration of S(+)-ibuprofen in plasma was modelled according to a sigmoidal Emax equation. The mean plasma unbound concentration of S(+)-ibuprofen required to inhibit platelet TXB2 generation by 50% (EC50) was 9.8 +/- 1.0 micrograms l-1.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship between the pharmacokinetics of ibuprofen enantiomers and the dose of racemic ibuprofen in humans.

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.