bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential selectivity of cytochrome P450 inhibitors against probe substrates in human and rat liver microsomes
Authors: Eagling Victoria A. , Tjia John F. , Back David J.
Published: March 2003

Aims
 Chemical inhibitors of cytochrome P450 (CYP) are a useful tool in defining the role of individual CYPs involved in drug metabolism. The aim of the present study was to evaluate the selectivity and rank the order of potency of a range of isoform‐selective CYP inhibitors and to compare directly the effects of these inhibitors in human and rat hepatic microsomes.

Methods
 Four chemical inhibitors of human cytochrome P450 isoforms, furafylline (CYP1A2), sulphaphenazole (CYP2C9), diethyldithiocarbamate (CYP2E1), and ketoconazole (CYP3A4) were screened for their inhibitory specificity towards CYP‐mediated reactions in both human and rat liver microsomal preparations. Phenacetin O‐deethylation, tolbutamide 4‐hydroxylation, chlorzoxazone 6‐hydroxylation and testosterone 6β‐hydroxylation were monitored for enzyme activity.

Results
 Furafylline was a potent, selective inhibitor of phenacetin O‐deethylation (CYP1A2‐mediated) in human liver microsomes (IC50=0.48 μm ), but inhibited both phenacetin O‐deethylation and tolbutamide 4‐hydroxylation (CYP2C9‐mediated) at equimolar concentrations in rat liver microsomes (IC50=20.8 and 24.0 μm respectively). Sulphaphenazole demonstrated selective inhibition of tolbutamide hydroxylation in human liver microsomes but failed to inhibit this reaction in rat liver microsomes. DDC demonstrated a low level of selectivity as an inhibitory probe for chlorzoxazone 6‐hydroxylation (CYP2E1‐mediated). DDC also inhibited testosterone 6β‐hydroxylation (CYP3A‐mediated) in man and rat, and tolbutamide 4‐hydroxylase activity in rat. Ketoconazole was a very potent, selective inhibitor of CYP3A4 activity in human liver (IC50=0.04 μm ). Although inhibiting CYP3A in rat liver it also inhibited all other reactions at concentrations ≤5 μm.

Conclusions
 It is evident that CYP inhibitors do not exhibit the same selectivity in human and rat liver microsomes. This is due to differential selectivity of the inhibitors and/or differences in the CYP isoform responsible for metabolism in the different species.
Terfenadine–antidepressant interactions: an in vitro inhibition study using human liver microsomes
Authors: Jurima‐Romet Malle , Wright Marcy , Neigh Scott
Published: March 2003

Aims
 Inhibition of the metabolism of terfenadine has been associated with torsades de pointes ventricular arrhythmias. The aim of this study was to assess in vitro the potency of the antidepressants nefazodone, sertraline and fluoxetine in inhibiting terfenadine biotransformation.

Methods
 Human liver microsomes were incubated with terfenadine and the antidepressants at various concentrations. Formation of the two major metabolites of terfenadine was determined by h.p.l.c.

Results
 The apparent Km for microsomes from four human livers was 11±5 and 18±3 μm (mean±s.e.mean) for the N‐dealkylation and C‐hydroxylation pathways, respectively. Nefazodone, sertraline and fluoxetine inhibited terfenadine N‐dealkylation with Ki values of 10±4, 10±3 and 68±15 μm respectively. Inhibition of the C‐hydroxylation pathway yielded noncompetitive Ki values of 41±4, 67±13 and 310±40 μm respectively.

Conclusions
 Nefazodone and sertraline were moderately weak in vitro inhibitors of terfenadine metabolism while fluoxetine was a very weak inhibitor. Clinically significant interaction of terfenadine is more likely with nefazodone than sertraline or fluoxetine since therapeutic plasma levels of nefazodone are comparatively higher.
Trying to improve compliance with prophylactic penicillin therapy in children with sickle cell disease
Authors: Berkovitch Matitiahu , Papadouris Dimitrios , Shaw Dianne , Onuaha Nzenalu , Dias Carla , Olivieri Nancy F.
Published: March 2003

Aims
 To evaluate compliance with prophylactic penicillin therapy in sickle cell disease (SCD) in children.

Methods
 Forty‐five children aged 37±19 (9–84) months [mean±s.d; range] with homozygous SCD were recruited. After a baseline period of 2 months the patients were randomized to either the intervention or non‐intervention group. The intervention consisted of a slide show explaining the pathogenesis of sickle cell disease and its complications; weekly phone calls by the clinic social worker; and a calendar. Compliance was again evaluated after the 2 month intervention period and after a further 2 month monitoring period without intervention. Compliance was monitored using the Medication Event Monitoring System. At the end of the 6 months, parents in both groups completed a questionnaire the aims of which were to determine knowledge and understanding of sickle cell disease and previous experience with infection. Patient admissions to the hospital during the study were recorded.

Results
 Compliance during the 2 month baseline assessment was 66.0±32.5 (1.3–98.2)% and 69.3±25.4 (19.8–96.5)% in the intervention (n=13) and non‐intervention (n=10) groups respectively (P=0.79). During the next 2 months, compliance in the intervention group (n=11) was 79.0±31.4 (11.0–100.0)% and in the non‐intervention group (n=9) was 66.0±20.2 (42.2–96.8)% (P=0.297). In the final 2 month monitoring period compliance was 82.0±34.7 (3.8–100.0)% and 65.8±25.3 (25.0–98.2)% in the intervention (n=7) and the non‐intervention (n=6) groups respectively (P=0.366). No statistically significant differences were found when comparing compliance between the groups.

Conclusions
 Compliance with prophylactic antibiotic therapy in children with sickle cell disease is highly variable and its evaluation is problematic.
Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers
Authors: Ouellet* Daniele , Hsu Ann , Qian Jiang , Locke Charles S. , Eason Carolyn J. , Cavanaugh John H. , Leonard John M. , Granneman G. Richard
Published: March 2003

Aims To assess the effects of the protease inhibitor ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers.

Methods This was an open‐label, single centre study in 23 subjects who received two single doses of oral contraceptive containing 50 μg ethinyl oestradiol on Day 1 (alone) and on Day 29 during concomitant ritonavir. Each subject received 16 days of every 12 h doses of ritonavir from Day 15 through Day 30. Blood samples were collected for serum ethinyl oestradiol concentrations for 48 h after each dose and for plasma ritonavir on Day 29 at 0 and 4 h postdose.

Results Statistically significant decreases in ethinyl oestradiol meanCmax(−32%) and mean AUC (−41%), and a statistically significant increase in the mean terminal elimination rate constant (+31%) were observed during concomitant ritonavir. The harmonic mean terminal half‐life decreased from 17 h to 13 h during concomitant ritonavir. No statistically significant change was noted intmax. The ratios of means (95% confidence intervals) forCmaxand AUC were 0.682 (0.612–0.758) and 0.595 (0.506–0.694), respectively. The changes in ethinyl oestradiol pharmacokinetics were consistent with an increase in clearance from enzymatic induction of glucuronidation and/or cytochrome P450 hydroxylation. Mean steady‐state ritonavir concentrations of 6.5 and 13.4 μg ml−1were observed at 0 and 4 h postdose, respectively.

Conclusions Considering the extent of the decrease in ethinyl oestradiol concentrations, the use of alternate contraceptive measures should be considered when ritonavir is being administered.
Bias in reporting clinical trials
Authors: Bardy A. H.
Published: March 2003

Aims
 The primary aim of the present study was to identify possible occurrence of selective reporting of the results of clinical trials to the Finnish National Agency for Medicines. Selective reporting may lead to poorly informed action or inaction by regulatory authorities.

Methods
 In 1987, 274 clinical drug trials were notified to the Finnish National Agency for Medicines. By December 1993, final reports had been received from 68 of these trials and statements that the trial had been suspended from 24 trials. The sponsors of the non‐reported trials were requested to report the outcome. The outcomes, if any, of all reported and non‐reported trials were classified as positive, inconclusive or negative.

Results
 The total number of trials with positive, inconclusive or negative outcome were 111, 33 and 44, respectively; the outcomes of 86 trials could not be assessed. Final reports were received from 42/111 (38%) trials with positive, 6/33 (18%) with inconclusive and 9/44 (20%) with negative outcomes.

Conclusions
 Substantial evidence of selective reporting was detected, since trials with positive outcome resulted more often in submission of final report to regulatory authority than those with inconclusive or negative outcomes.
Effects of acipimox on haemorheology and plasma lipoproteins in patients with mixed hyperlipoproteinaemia
Authors: Otto  , Parhofer  , Ritter  , Richter  , Schwandt
Published: March 2003

Aims Epidemiological data have shown that haemorheological disorders are associated with an increased risk of atherosclerosis. We evaluated the effect of the nicotinic acid derivative acipimox on haemorheological and lipid parameters in 18 patients with mixed hyperlipoproteinaemia using a randomized, double‐blind, placebo‐controlled, cross‐over study protocol.

Methods Patients (7 women, 11 men, aged 49.3±3.0 years) were investigated with acipimox (dose adjusted to weight, 500 or 750 mg daily) compared with placebo treatment each for 12 weeks. Lipid parameters, whole blood viscosity, plasma viscosity, fibrinogen, and red cell aggregation at native and standardized (0.45) haematocrit as well as red cell filterability were measured at baseline, at week 12 (change of therapy), and at week 24.

Results Total cholesterol concentration (8.30±0.32 vs 8.72±0.36 mmol/l−1 ) and apolipoprotein B (198.5±9.9 vs 217±9.9 mg dl−1 ) were significantly lower (P<0.05) during acipimox therapy compared with placebo, no significant changes were observed for triglycerides and low‐density lipoprotein [LDL] cholesterol. However, total high‐density lipoprotein [HDL] cholesterol (1.24±0.05 vs 1.10±0.05 mmol l−1, P<0.001) as well as HDL2 and HDL3 cholesterol (P<0.05) were significantly higher during acipimox therapy. The LDL cholesterol to HDL cholesterol ratio significantly improved during acipimox therapy (4.63±0.25 vs 5.49±0.26, P<0.001). Red cell aggregation at native and standardized haematocrit were the only haemorheological parameters which improved during acipimox therapy in comparison with placebo (shear rate 3 s−1: 10.69±0.40 vs 11.50±0.44 U, P<0.05, for native red cell aggregation; 10.40±0.36 vs 11.28±0.39 U, P<0.05, for standardized red cell aggregation).

Conclusions We conclude, that the cardiovascular risk profile improves during acipimox therapy due to an elevation in HDL cholesterol and its subfractions as well as a decrease in red cell aggregation.
Comparison of (S)‐mephenytoin and proguanil oxidation in vitro: contribution of several CYP isoforms
Authors: Coller  , Somogyi  , Bochner
Published: March 2003

Aims To compare the oxidative metabolism of (S)‐mephenytoin and proguanil in vitro and to determine the involvement of various cytochrome P450 isoforms.

Methods The kinetics of the formation of 4′‐hydroxymephenytoin and cycloguanil in human liver microsomes from 10 liver samples were determined, and inhibition of formation was studied using specific chemical inhibitors and monoclonal antibodies directed towards specific CYP450 isoforms. Expressed CYP450 enzymes were used to characterize further CYP isoform contribution in vitro. Livers were genotyped for CYP2C19 using PCR amplification of genomic DNA followed by restriction endonuclease digestion.

Results All livers were wildtype with respect to CYP2C19, except HLS#5 whose genotype was CYP2C19*1/CYP2C19*2. The Km, Vmax and CLint values for the formation of 4′‐hydroxymephenytoin from (S)‐mephenytoin and the formation of cycloguanil from proguanil ranged from 50.8 to 51.6 and 43–380 μm, 1.0–13.9 and 0.5–2.5 nmol mg−1 h−1, and 20.2–273.8 and 2.7–38.9 μl h−1 mg−1, respectively. There was a significant association between the Vmax values of cycloguanil and 4′‐hydroxymephenytoin formation (rs=0.95, P=0.0004). Cycloguanil formation was inhibited significantly by omeprazole (CYP2C19/3A), troleandomycin (CYP3A), diethyldithiocarbamate (CYP2E1/3A), furafylline (CYP1A2), and (S)‐mephenytoin. 4′‐Hydroxymephenytoin formation was inhibited significantly by omeprazole, diethyldithiocarbamate, proguanil, furafylline, diazepam, troleandomycin, and sulphaphenazole (CYP2C9). Human CYP2E1 and CYP3A4 monoclonal antibodies did not inhibit the formation of cycloguanil or 4′‐hydroxymephenytoin, and cycloguanil was formed by expressed CYP3A4 and CYP2C19 supersomes. However, only expressed CYP2C19 and CYP2C19 supersomes formed 4′‐hydroxymephenytoin.

Conclusions The oxidative metabolism of (S)‐mephenytoin and proguanil in vitro is catalysed by CYPs 2C19 and 1A2, with the significant association between Vmax values suggesting that the predominant enzymes involved in both reactions are similar. However the degree of selectively of both drugs for CYP isoforms needs further investigation, particularly the involvement of CYP3A4 in the metabolism of proguanil. We assert that proguanil may not be a suitable alternative to (S)‐mephenytoin as a probe drug for the CYP2C19 genetic polymorphism.
A review of the pharmacology and clinical activity of new chemotherapy agents for the treatment of colorectal cancer
Authors: Adjei Alex A.
Published: March 2003

Colorectal carcinoma is an important cause of cancer morbidity and mortality. 5‐fluorouracil has been the major chemotherapeutic agent for the treatment of colorectal carcinoma for the past four decades. This regimen is noncurative, and its impact on survival is unclear. Attempts at identifying more effective chemotherapeutic agents for colorectal cancer have yielded oral formulations and prodrugs of 5‐fluorouracil with apparently equivalent efficacy. Specific thymidylate synthase inhibitors are now available. Platinum analogues with activity in colorectal carcinoma, and no cross‐resistance to the antimetabolites have also been developed. The topoisomerase I inhibitors represent a new class of agents with a novel mechanism of action. These agents are in phase II and Phase III clinical trials, others have been approved for clinical use within the last 3 years.
Characterization of the cytochrome P450 enzymes involved in the in vitro metabolism of rosiglitazone
Authors: Baldwin  , Clarke  , Chenery
Published: March 2003

Aims To identify the human cytochrome P450 enzyme(s) involved in the in vitro metabolism of rosiglitazone, a potential oral antidiabetic agent for the treatment of type 2 diabetes‐mellitus.

Method The specific P450 enzymes involved in the metabolism of rosiglitazone were determined by a combination of three approaches; multiple regression analysis of the rates of metabolism of rosiglitazone in human liver microsomes against selective P450 substrates, the effect of selective chemical inhibitors on rosiglitazone metabolism and the capability of expressed P450 enzymes to mediate the major metabolic routes of rosiglitazone metabolism.

Result The major products of metabolism following incubation of rosiglitazone with human liver microsomes were para‐hydroxy and N‐desmethyl rosiglitazone. The rate of formation varied over 38‐fold in the 47 human livers investigated and correlated with paclitaxel 6α‐hydroxylation (P<0.001). Formation of these metabolites was inhibited significantly (>50%) by 13‐cis retinoic acid, a CYP2C8 inhibitor, but not by furafylline, quinidine or ketoconazole. In addition, both metabolites were produced by microsomes derived from a cell line transfected with human CYP2C8 cDNA. There was some evidence for CYP2C9 playing a minor role in the metabolism of rosiglitazone. Sulphaphenazole caused limited inhibition (<30%) of both pathways in human liver microsomes and microsomes from cells transfected with CYP2C9 cDNA were able to mediate the metabolism of rosiglitazone, in particular the N‐demethylation pathway, albeit at a much slower rate than CYP2C8. Rosiglitazone caused moderate inhibition of paclitaxel 6α‐hydroxylase activity (CYP2C8; IC50=18 μm ), weak inhibition of tolbutamide hydroxylase activity (CYP2C9; IC50=50 μm ), but caused no marked inhibition of the other cytochrome P450 activities investigated (CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A and 4A).

Conclusion CYP2C8 is primarily responsible for the hydroxylation and N‐demethylation of rosiglitazone in human liver; with minor contributions from CYP2C9.
Therapeutic drug monitoring in drug overdose
Authors: Dawson Andrew H. , Whyte Ian M.
Published: March 2003

The treatment of poisoned patients is still largely defined by history, clinical assessment and interpretation of ancillary investigations. Measurement of drug concentrations is clinically important for relatively few compounds. Most measurements form an adjunct to and should not be considered a substitute for clinical assessment. Drug concentrations are particularly important for those compounds where the concentration is predictive of serious toxicity in an otherwise asymptomatic patient.
Distribution and excretion of fluoxetine and norfluoxetine in human milk
Authors: Kristensen  , Ilett  , Hackett  , Yapp  , Paech  , Begg
Published: March 2003

Aims To characterize milk/plasma (M/P) ratio and infant dose, for fluoxetine and norfluoxetine, in breast‐feeding women taking fluoxetine for the treatment of depression, and to determine the plasma concentration of these drugs in their infants.

Methods Fourteen women (mean age 32.2 years) taking fluoxetine (mean dose 0.51 mg kg−1 day−1 ) and their infants (mean age 3.4 months) were studied. Fluoxetine and norfluoxetine in plasma and milk were measured by high‐performance liquid chromatography over a 24 h dose interval in four patients, and by single point data collection in 10 patients. Infant exposure was estimated as the product of estimated milk production, and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight‐adjusted maternal dose.

Results Mean M/P values of 0.68 (95% CI 0.52–0.84) and 0.56 (95% CI 0.35–0.77) were calculated for fluoxetine and norfluoxetine, respectively. Mean total infant exposure (fluoxetine equivalents) was estimated to be 6.81% (range 2.15–12%) of the weight‐adjusted maternal dose of fluoxetine. Contributions from fluoxetine and norfluoxetine were approximately equal. Fluoxetine (range 20–252 μg l−1 ) was detected in five of the nine infants from whom samples were collected, and norfluoxetine (range 17–187 μg l−1 ) was detected in seven of the nine infants. The highest of these concentrations was about 70% of the maternal plasma concentrations.

Conclusions The mean combined dose of fluoxetine and norfluoxetine transmitted to infants via breast milk is below the 10% notional level of concern. However, there was considerable interpatient variability in estimated infant dose and in some of the patients, the dose was >10%. Further, since adverse effects have been observed in breast‐fed infants, careful monitoring of the infants is mandatory. Neonates exposed to these drugs in utero had higher concentrations of fluoxetine and norfluoxetine and are at greater risk of adverse effects.
Impact of guidelines implemented in a Paris university hospital: application to the use of antiemetics by cancer patients
Authors: Debrix  , Flahault  , Becker  , Schwartz  , Kanfer  , Milleron
Published: March 2003

Aims To assess the impact with time of guidelines on antiemetic use in an 850‐bed Paris university hospital with a high proportion of cancer patients.

Methods Guidelines on the use of antiemetics available in cancer chemotherapy were drafted according to the Delphi technique. Their implementation was based upon a patient‐specific antiemetic prescription form. To assess the impact of guideline implementation over time, discrepancies between current practice and the guidelines were compared before guideline implementation (between March and August 1995) and after implementation (between March and August 1997, and March and August 1998).

Results Before the Delphi panel’s guidelines were implemented, 5‐HT3 antagonists were inappropriately administered in 70% of cases. After guideline implementation, this proportion dropped significantly (P<0.0001, Fisher’s exact test) to 22% between March and August 1997 and 28% between March and August 1998.

Conclusions Implementation of guidelines seems to have resulted in significant changes with time, although a causal relationship has not been demonstrated. The development of guidelines by our hospital’s multidisciplinary working group helped the various consultants to adjust medical practices to take account of these changes.
Population pharmacokinetics of enterally administered cisapride in young infants with gastro‐oesophageal reflux disease
Authors: Preechagoon  , Charles  , Piotrovskij  , Donovan  , Van Peer
Published: March 2003

Aims To investigate the pharmacokinetics of enterally administered cisapride suspension in young infants being treated for gastro‐oesophageal reflux disease.

Methods Plasma cisapride concentrations in 49 subjects (weight: 825–5010 g; n=108 samples, median two per patient; concentration: 14.8–170 ng ml−1 ) were fitted to a one‐compartment model with first‐order absorption and elimination in the NONMEM program using a logarithmic transformation of the observed and predicted concentrations. Fitting was achieved using the first order conditional estimation (FOCE) method with interaction between the interpatient and intrapatient variabilities. The interpatient variance of clearance (CL/F ) and volume of distribution (V /F ) and their covariance were estimated using an exponential error model. Intrapatient (residual) variance was estimated using an additive model.

Results The clearance of cisapride was shown to be linearly related to current body weight, slope: 0.538. The typical population values of CL/F, V /F and Ka (absorption rate constant) were 0.538 l h−1 kg−1, 21.9 l, and 2.58 h−1, respectively. The population coefficients of variation (CV%) for CL/F and V /F were 34.4% and 84.3%, respectively. The squared coefficient of correlation between random effects for CL/F and V /F was 0.45. The intrapatient variance was 0.15. V /F and Ka were not influenced significantly by any patient characteristic.

Conclusions Cisapride pharmacokinetics in infants with reflux disease were satisfactorily described by a one‐compartment model. Current weight should be taken into account when calculating maintenance cisapride doses in these infants.
Pharmacokinetic‐pharmacodynamic model for fantofarone cardiac and brachial haemodynamic effects in healthy volunteers
Authors: Bellissant Eric , Giudicelli Jean‐François
Published: March 2003

Aims To investigate the pharmacokinetics of SR 33671, the main active metabolite of the calcium antagonist fantofarone, and the relationships between its concentrations and pharmacodynamic effects after a single oral administration of two doses (100 and 300 mg) of fantofarone.

Methods A placebo‐controlled, randomized, double‐blind and crossover study was performed in six healthy volunteers. SR 33671 plasma concentrations (C, ng ml−1 ) and effects (E) on heart rate (HR, beats min−1 ), PR interval duration (ms), brachial artery flow (BAF, ml min−1 ) and brachial vascular resistance (BVR, mmHg s ml−1 ) were determined repeatedly after drug intake. Haemodynamic effects were expressed as percent changes from initial values. Bi‐exponential (pharmacokinetics), and linear [E=S.C+E0, for cardiac effects] or sigmoid [E=Emax.Cγ/(
CEγ50+Cγ ), for haemodynamic effects] models were fitted to individual data.

Results Peak plasma concentrations and areas under the curve up to 24 h were (mean±s.d.) 16±10 ng ml−1 and 157.50±89.13 ng ml−1 h, and 63±11 ng ml−1 and 535.50±135.11 ng ml−1 h, after 100 and 300 mg, respectively. Terminal half‐life was approximately 4 h. For pharmacodynamics, we obtained: S=−0.201±0.057 beats min−1/ng ml−1 for HR, S=0.526±0.114 ms/ng ml−1 for PR interval duration, Emax=42±6%, CE50=8.8±7.2 ng ml−1 and γ=2.2±1.5 for BAF, and Emax=−28±4%, CE50=5.8±5.1 ng ml−1 and γ=3.4±1.8 for BVR. At a SR 33671 concentration of 15 ng ml−1, BVR is decreased by 27% whereas HR is reduced by less than 3 beats min−1 and PR interval duration is increased by less than 8 ms.

Conclusions Fantofarone is able to induce submaximal peripheral vasodilating effects at doses that are devoid of any clinically significant cardiac effect.
Effect of diclofenac, disulfiram, itraconazole, grapefruit juice and erythromycin on the pharmacokinetics of quinidine
Authors: Damkier Per , Hansen Lone L. , Brøsen Kim
Published: March 2003

Aims In vitro studies suggest that the oxidation of quinidine to 3‐hydroxyquinidine is a specific marker reaction for CYP3A4 activity. To assess the possible use of this reaction as an in vivo marker of CYP3A4 activity, we studied the involvement of cytochromes CYP2C9, CYP2E1 and CYP3A4 in the in vivo oxidative metabolism of quinidine.

Methods An open study of 30 healthy young male volunteers was performed. The pharmacokinetics of a 200 mg single oral dose of quinidine was studied before and during daily administration of 100 mg diclofenac, a CYP2C9 substrate (n=6); 200 mg disulfiram, an inhibitor of CYP2E1 (n=6); 100 mg itraconazole, an inhibitor of CYP3A4 (n=6); 250 ml single strength grapefruit juice twice daily, an inhibitor of CYP3A4 (n=6); 250 mg of erythromycin 4 times daily, an inhibitor of CYP3A4 (n=6). Probes of other enzyme activities, caffeine (CYP1A2), sparteine (CYP2D6), mephenytoin (CYP2C19), tolbutamide (CYP2C9) and cortisol (CYP3A4) were also studied.

Results Concomitant administration of diclofenac reduced the partial clearance of quinidine by N‐oxidation by 27%, while no effect was found for other pharmacokinetic parameters of quinidine. Concomitant administration of disulfiram did not alter any of the pharmacokinetic parameters of quinidine. Concomitant administration of itraconazole reduced quinidine total clearance, partial clearance by 3‐hydroxylation and partial clearance by N‐oxidation by 61, 84 and 73%, respectively. The renal clerance was reduced by 60% and the elimination half‐life increased by 35%. Concomitant administration of grapefruit juice reduced the total clearance of quinidine and its partial clearance by 3‐hydroxylation and N‐oxidation by 15, 19 and 27%, respectively. The elimination half‐life of quinidine was increased by 19%. The caffeine metabolic index was reduced by 25%. Concomitant administration of erythromycin reduced the total clearance of quinidine and its partial clearance by 3‐hydroxylation and N‐oxidation by 34, 50 and 33%, respectively. Cmax was increased by 39%.

Conclusions The results confirm an important role for CYP3A4 in the oxidation of quinidine in vivo, and this applies particularly to the formation of 3‐hydroxyquinidine. While a minor contribution of CYP2C9 to the N‐oxidation of quinidine is possible, a major involvement of the CYP2C9 or CYP2E1 enzymes in the oxidation of quinidine in vivo is unlikely.
Cough and angiotensin II receptor antagonists: cause or confounding?
Authors: Mackay  , Pearce  , Mann
Published: March 2003

Aims Cough is one of the most frequent side effects associated with angiotensin converting enzyme inhibitors (ACEIs) but is not thought to be associated with losartan, an angiotensin II receptor antagonist (ARA). This study compares reports of cough with losartan and three ACEIs used in general practice.

Methods Studies have been conducted for losartan, and three ACEIs enalapril, lisinopril and perindopril, using the technique of Prescription‐Event Monitoring. Patients were identified using dispensed prescription data. Questionnaires were sent to patients’ general practitioners 6 months after the date of first prescription. Cases of cough within the first 60 days of treatment with losartan resulting in withdrawal of the drug were followed up with additional questionnaires. Incidence rates for reports of cough were calculated. In order to reduce the impact of carry‐over effects, rate ratios were calculated for first reports of cough between days 8 and 60 using losartan as the index drug.

Results The cohort for each drug exceeded 9000 patients. Age and sex distributions and indications for prescribing the four drugs were similar. Cough was the most frequent reason for discontinuation of losartan and the most frequently reported event in the first month of treatment with this drug. When reports of cough between days 1–7 were excluded, rates of cough were significantly higher for the three ACEIs when compared with losartan (rate ratios 1.5, 4.8 and 5.7, all P<0.03). 101 patients had discontinued losartan due to cough. 91% of these had previously been prescribed an ACEI and 86% had previously experienced ACEI cough.

Conclusions Carry‐over accounted for the observed excess of reports of cough with losartan. Rates of cough between days 8 and 60 were significantly higher for the three ACEIs compared with losartan. Confounding factors associated with comparative observational cohort studies are discussed.
Platelet α2‐adrenoceptor alterations in patients with essential hypertension
Authors: Varani Katia , Gessi Stefania , Caiazza Alberto , Rastelli Gianni , Portaluppi Francesco , Borea Pier Andrea
Published: March 2003

Aims The purpose of this study was to determine whether human platelet α2‐adrenoceptors were altered in essential hypertension. A systematic analysis was carried out on 165 normotensives and 124 untreated primary hypertensives.

Methods The study was performed at different levels: i) density and affinity of platelet α2‐adrenoceptors were determined by receptor binding assays using the full α2‐adrenoceptor agonist [3H]‐UK 14304 and a thermodynamic analysis of data was carried out to evaluate if binding mechanisms at the molecular level were altered during hypertension; ii) the functionality of Gi proteins coupled to α2‐adrenoceptors and iii) forskolin‐stimulated cAMP levels were measured.

Results Platelet α2‐adrenoceptors mean density (Bmax ) and affinity (Kd ) (±s.e.mean) were significantly lower and higher, respectively, in normotensive than in hypertensive subjects [Bmax=327±4 vs 435±5 fmol mg−1 of protein (P<0.01) and Kd=3.76±0.05 vs 6.50±0.15 nm (P<0.01), respectively]. The 50% stimulating concentration of adrenaline on [35S]‐GTPγS binding to Gi proteins was significantly (P<0.01) lower in normotensives (12±2 nm ) than in hypertensives (110±10 nm ). The 50% inhibiting concentration of adrenaline on forskolin‐stimulated cAMP levels was significantly (P<0.01) lower in normotensive (22±2 nm ) than in hypertensive subjects (200±25 nm ).

Conclusions Present analysis, including receptorial and functional data, provides evidence that marked alterations occur in platelet α2‐adrenoceptors of hypertensive subjects.
The effect of steady‐state ropinirole on plasma concentrations of digoxin in patients with Parkinson’s disease
Authors: Taylor  , Beerahee  , Citerone  , Davy  , Fitzpatrick  , Lopez‐Gil  , Stocchi
Published: March 2003

Aims The aim of this single‐blind study was to assess the effect of ropinirole, a novel treatment for Parkinson’s disease, on the steady‐state pharmacokinetics and safety of digoxin in 10 patients with Parkinson’s disease.

Methods There were three parts to the study: digoxin once daily plus placebo three times daily for 1 week; digoxin once daily plus ropinirole three times daily for 6 weeks; and digoxin once daily plus placebo three times daily for 1 week. Serial blood samples were collected over 24 h at the end of each part of the study for pharmacokinetic assessment. Pre‐dose blood samples were collected on specific days throughout the study to assess the attainment of steady‐state plasma levels of digoxin. The primary endpoints were AUC(0, τ) and Cmax for digoxin.

Results There was a mean decrease of 10% in digoxin AUC (0, τ) (90% CI: 0.79, 1.01) and a 25% decrease in digoxin Cmax (90% CI: 0.58, 0.97) when ropinirole was co‐administered, compared with digoxin alone. Cmin plasma values for digoxin, however, were fairly constant throughout the study (point estimates 0.99, 95% CI: 0.85, 1.15). Changes in trough levels of digoxin are believed to be the most reliable way of assessing steady‐state concentrations of digoxin, and therefore the clinical significance of an interaction. Changes in Cmax are too readily influenced by other factors.

Conclusions These results therefore indicate that on pharmacokinetic grounds no dose adjustment is necessary for digoxin co‐administered with ropinirole.
Clinical and pharmacokinetic results with a new ultrashort‐acting calcium antagonist, clevidipine, following gradually increasing intravenous doses to healthy volunteers
Authors: Ericsson  , Fakt  , Jolin‐Mellgård  , Nordlander  , Sohtell  , Sunzel  , Regårdh
Published: March 2003

Aims To investigate the tolerability and safety of clevidipine in healthy male volunteers during intravenous infusion at gradually increasing dose rates and to obtain preliminary information on the pharmacokinetics and pharmacodynamic effects of the drug.

Methods Twenty‐five subjects were enrolled in the study and twenty‐one of them were included twice, resulting in a total of forty‐six study entries encompassing 20 min infusions of clevidipine at target dose rates ranging from 0.12 to 48 nmol min−1 kg−1. Haemodynamic variables and adverse events were recorded throughout the study. Concentrations of clevidipine and its primary metabolite, H 152/81, were followed in whole blood, and the pharmacokinetics were evaluated by non‐compartmental and compartmental analysis. An Emax model was fitted to the effect on mean arterial pressure (MAP) over heart rate (HR) and the corresponding blood concentrations of clevidipine.

Results Clevidipine was administered up to a target dose rate of 48 nmol min−1 kg−1, where a pre‐determined escape criterion was reached (HR>120 beats min−1 ) and the study was stopped. The most common adverse events were flush and headache, which can be directly related to the mechanism of action of clevidipine. There was a linear relationship between blood concentration and dose rate in the range studied. The median clearance value determined by non‐compartmental analysis was 0.125 l min−1 kg−1. Applying the population approach to the sparse data on clevidipine concentrations, an open two compartment pharmacokinetic model was found to be the best model in describing the disposition of the drug. The population mean clearance value determined by this method was 0.121 l min−1 kg−1, and the volume of distribution at steady state was 0.56 l kg−1. The initial half‐life, contributing by more than 80% to the total area under the blood concentration‐time curve following i.v. bolus administration, was 1.8 min, and the terminal half‐life was 9.5 min. At the highest dose rates, MAP was reduced by approximately 10%, and the HR reached the pre‐determined escape criterion for this study (>120 beats min−1 ).

Conclusions Clevidipine is well tolerated and safe in healthy volunteers at dose rates up to at least 48 nmol min−1 kg−1. The pharmacokinetics are linear over a wide dose range. Clevidipine is a high clearance drug with extremely short half‐lives. The effect of clevidipine on the blood pressure was marginal, probably due to a compensatory baroreflex activation in this population of healthy volunteers. A simple Emax model adequately describes the relationship between the pharmacodynamic response (MAP/HR) and the blood concentrations of clevidipine.
Microsomal prediction of in vivo clearance of CYP2C9 substrates in humans
Authors: Carlile David J. , Hakooz Nancy , Bayliss Martin K. , Houston J. Brian
Published: March 2003

Aims To assess the utility of human hepatic microsomes for predicting in vivo intrinsic clearance (CLint ) via the use of four cytochrome P450 2C9 substrates: phenytoin, tolbutamide (S)‐ibuprofen (two pathways) and diclofenac, and to examine the role of exogenous albumin within the microsomal incubation.

Methods V max, Km and CLint (defined as V max/Km ratio) were estimated under initial rate conditions for five pathways of metabolism in a bank of 15 human hepatic microsomal samples and were scaled to in vivo units using the microsomal protein index. Non‐metabolic related binding in microsomes was measured for phenytoin and tolbutamide in the presence and absence of albumin.

Results Microsomal CLint values differed by over two orders of magnitude, with the means ranging from 0.18 (phenytoin) to 40.70 (diclofenac) μl min−1 mg−1 microsomal protein. When these data were scaled and compared with published in vivo studies a similar rank order was obtained, however, the actual CLint tended to be underpredicted. While the in vivo unbound Km for phenytoin, 1–5 μm is substantially lower than the value determined in microsomes based on total concentrations (56 μm ), correction for the in vitro binding reduces this value to 20 μm and 6 μm in the absence and presence of albumin, respectively. Similar trends were seen with tolbutamide Km.

Conclusions An appreciation of the utility of in vitro prediction can be best achieved when the range of CLint values predicted from the individual hepatic microsomal samples are compared with the range of individual in vivo CLint values reported in the literature. The degree of underprediction is less evident using the range than the mean data and no consistent advantage in adding albumin to the incubation media is apparent.
Target concentration intervention: beyond Y2K
Authors: Holford Nicholas H. G.
Published: March 2003

Target concentration intervention (TCI) is proposed as an alternative conceptual strategy to therapeutic drug monitoring (TDM). It is argued that the idea of a therapeutic range has limited the interpretation of measured drug concentrations and diminished the anticipated clinical benefit to patients by use of an oversimplified pharmacodynamic model. TCI on the other hand embraces pharmacokinetic and pharmacodynamic concepts and uses the idea of a target effect and associated target concentration to make rational individual dose decisions.
Induction of zidovudine glucuronidation and amination pathways by rifampicin in HIV‐infected patients
Authors: Gallicano Keith D. , Sahai Jan , Shukla Vijay K. , Seguin Isabelle , Pakuts Attila , Kwok David , Foster Brian C. , Cameron D. William
Published: March 2003

Aims
 The objective of the study was to determine the effect of multiple doses of rifampicin on the steady‐state pharmacokinetics of zidovudine and its 5′‐glucuronosyl (GZDV) and 3′‐amino (AMT) metabolites.

Methods
 Eight asymptomatic HIV‐infected patients (seven male, one female) participated in this three‐period longitudinal study. Each patient received zidovudine (200 mg every 8 h) for 14 days (period 1), followed by rifampicin (600 mg every 24 h) with zidovudine for 14 days (period 2), and then zidovudine alone for a further 14 days (period 3). Blood and urine samples were collected over 6 h on the last day of each period for measurements of zidovudine and GZDV by h.p.l.c.‐u.v. and AMT by h.p.l.c.‐m.s‐m.s.

Results
 Compared with zidovudine‐alone values in period 1, 14 days of coadministration with rifampicin significantly increased zidovudine oral clearance (89%) and formation clearances to GZDV (100%) and AMT (82%). Correspondingly, there were decreases in maximum plasma concentration (43%), AUC (47%) and urine recovery (37%) of zidovudine. GZDV/zidovudine and AMT/zidovudine AUC ratios increased by 99% and 36%, respectively, despite a significant 29% decrease in AMT AUC. After stopping rifampicin for 14 days, values of these pharmacokinetic parameters returned to within 26% of baseline. Over the three periods AMT plasma levels were <18 ng ml−1 (n=6) and <40 ng ml−1 (n=2), and molar AMT/zidovudine AUC ratios ranged from 1.7% to 4.5%.

Conclusions
 Rifampicin induced zidovudine glucuronidation and amination pathways resulting in decreased plasma and urine exposures to zidovudine. AMT plasma exposure decreased because induction was more pronounced for the major GZDV metabolite. The magnitude of the residual inductive effect was minimal at 14 days after stopping rifampicin.
Paroxetine in human milk
Authors: Begg Evan J. , Duffull Stephen B. , Saunders Darren A. , Buttimore Rona C. , Ilett Kenneth F. , Hackett L. Peter , Yapp Patrick , Wilson Debbie A.
Published: March 2003

Aims
 The primary aims of the study were to estimate the exposure of infants to paroxetine via breast milk and to determine the maternal milk:plasma ratio (M/P) of paroxetine. Secondary aims were to compare single point and area under the curve (AUC) estimates of M/P, to assess variability of M/P in fore and hind milk, and to compare the observed M/P with that predicted by a model.

Methods
 Two studies were performed. In one study, six nursing mothers who were being treated with paroxetine were studied over a 24 h dose interval at steady‐state. The total amount of paroxetine in the milk was measured, which represented the ‘dose’ to the infant. The M/PAUC was calculated and compared with a predicted value. In the second study, four nursing mothers who were being treated with paroxetine, were studied at steady‐state, around a normal infant feeding time. A single plasma sample and a prefeed milk sample were taken approximately 3 h after the morning dose of paroxetine, and a postfeed milk sample taken around 1 h later. The dose received by the infant was estimated from the average milk concentrations of the pre and postfeed samples using standard assumptions, and M/P calculated directly. Plasma concentrations of paroxetine were measured in 8 of the 10 infants in the two studies.

Results
 The mean dose of paroxetine received by the infants in the first study was 1.13% (range 0.5–1.7) of the weight adjusted maternal dose. The mean M/PAUC was 0.39 (range 0.32–0.51). The predicted M/P was 0.22. The mean dose of paroxetine received by the infants in the second study was 1.25% (range 0.38–2.24) of the weight adjusted maternal dose. The mean M/P was 0.96 (range 0.31–3.33) and did not differ between fore and hind milk. The drug was not detected in the plasma of seven of the infants studied and was detected but not quantifiable (<4 μg l−1 ) in one infant. No adverse effects were observed in any of the infants.

Conclusions
 Measured M/P and estimated infant dose were similar in the two studies, although the range was wider for the single point study. Paroxetine can be considered ‘safe’ during breast feeding because the dose transferred to the infant is well below the recommended safety limit of 10% of the weight adjusted maternal dose, concentrations in the infants were generally undetectable, and no adverse effects were reported.
Inhibition of debrisoquine hydroxylation with quinidine in subjects with three or more functional CYP2D6 genes
Authors: Dalén P. , Dahl M.‐L. , Andersson K. , Bertilsson L.
Published: March 2003

Aims To study whether the CYP2D6 capacity in ultrarapid metabolizers of debrisoquine due to duplication/multiduplication of a functional CYP2D6 gene, can be ‘normalised’ by low doses of the CYP2D6 inhibitor quinidine and whether this is dose‐dependent.

Methods Five ultrarapid metabolizers of debrisoquine with 3, 4 or 13 functional CYP2D6 genes were given single oral doses of 5, 10, 20, 40, 80 and 160 mg quinidine. Four hours after quinidine intake, 10 mg debrisoquine was given. Urine was collected for 6 h after debrisoquine administration. Debrisoquine and its 4‐hydroxymetabolite were analysed by h.p.l.c. and the debrisoquine metabolic ratio (MR) was calculated.

Results Without quinidine the MR in the ultrarapid metabolizers ranged between 0.01 and 0.07. A dose‐effect relationship could be established for quinidine with regard to the inhibitory effect on CYP2D6 activity. To reach an MR of 1–2, subjects with 3 or 4 functional genes required a quinidine dose of about 40 mg, while the sister and brother with 13 functional genes required about 80 mg quinidine. After 160 mg quinidine, the MRs, in the subjects with 3, 3, 4, 13 and 13 functional genes, were 12.6, 10.1, 9.2, 2.4 and 2.2, respectively.

Conclusions A dose‐effect relationship could be established for quinidine inhibition of CYP2D6 in ultrarapid metabolizers. The clinical use of low doses of quinidine as an inhibitor of CYP2D6 might be considered in ultrarapid metabolizers taking CYP2D6 metabolized drugs rather than giving increased doses of the drug. Normalizing the metabolic capacity of CYP2D6, by giving a low dose of quinidine, may solve the problem of ‘treatment resistance’ caused by ultrarapid metabolism.
Effect of renal function on risedronate pharmacokinetics after a single oral dose
Authors: Mitchell D. Y. , St. Peter J. V. , Eusebio R.A. , Pallone K. A. , Kelly S. C. , Russell D. A. , Nesbitt J. D. , Thompson G. A. , Powell J. H.
Published: March 2003

Aims
 To determine the relationship between risedronate pharmacokinetics and renal function.

Methods
 Risedronate was administered to adult men and women (n=21) with various degrees of renal function (creatinine clearance 15–126 ml min−1 ) as a single oral dose of 30 mg. Serum samples were obtained for 72 h after dosing, and urine samples were collected for 72 h after dosing and then periodically for 6 weeks. Risedronate concentrations were determined using an enzyme‐linked immunosorbent assay (ELISA). Risedronate serum concentration‐time and urinary excretion rate‐time profiles were analysed simultaneously using nonlinear regression.

Results
 Renal clearance and volume of distribution were linearly related to creatinine clearance (r2=0.854, P<0.001; and r2=0.317, P<0.01, respectively). Decreases in predicted renal clearance and volume of distribution of 82 and 69%, respectively, were observed when creatinine clearance decreased from 120 to 20 ml min−1. A 64% decrease in predicted oral clearance was observed when creatinine clearance decreased from 120 to 20 ml min−1 (P=0.064). Iohexol clearance, a predictor of renal function, produced similar results to those observed with creatinine clearance. Risedronate was well tolerated by the study population.

Conclusions
 Risedronate renal clearance was significantly related to a decrease in renal function. There was a consistent reduction in oral clearance with a decrease in creatinine clearance. However, based on the regression analysis, generally no dosage adjustment appears to be necessary for most patients with mild or moderate renal impairment (creatinine clearance >20 ml min−1 ).
Drug interactions avoided–a useful indicator of good prescribing practice
Authors: Williams D. , Kelly A. , Feely J.
Published: March 2003

Aims  To develop an index of quality prescribing in general practice by investigating the incidence of potential drug interactions when medicines were coprescribed within the State supported General Medical Services (GMS) in Ireland.

Methods  We determined an odds ratio (OR), as a measure of the relative risk of being exposed to a potential interaction, comparing the use of the H2‐receptor antagonist, cimetidine, with that of the noninteracting agents ranitidine, famotidine and nizatidine in users and nonusers of warfarin, phenytoin and theophylline.

Results and conclusions  In 86 510 prescriptions for the H2–receptor antagonists potentially interacting drugs were dispensed to 8188 (9%) patients in the Eastern Health Board Region of the GMS. We found that prescribers were significantly less likely to use cimetidine (OR = 0.20,95% CI 0.17–0.21, P < 0.001) in those patients who were coprescribed warfarin, suggesting good prescribing practice within the GMS. Similarly there was preferential use of the noninteracting H2–receptor antagonists in patients receiving phenytoin or theophylline and the extent of this selective prescribing was in keeping with the rank order of severity of interaction with these drugs. This novel pharmacological index may be a sensitive marker of good prescribing practice.