Patient-specific electronic decision support reduces prescription of excessive doses.

OBJECTIVES: Prescription of excessive doses is the most common prescription error, provoking dose-dependent adverse drug reactions. Clinical decision support systems (CDSS) can prevent prescription errors especially when mainly clinically relevant warnings are issued. We have built and evaluated a CDSS providing upper dose limits personalised to individual patient characteristics thus guaranteeing for specific warnings. METHODS: For 170 compounds, detailed information on upper dose limits (according to the drug label) was compiled. A comprehensive software-algorithm extracted relevant patient information from the electronic chart (eg, age, renal function, comedication). The CDSS was integrated into the local prescribing platform for outpatients and patients at discharge, providing immediate dosage feedback. Its impact was evaluated in a 90-day intervention study (phase 1: baseline; phase 2: intervention). Outcome measures were frequency of excessive doses before and after intervention considering potential induction of new medication errors. Moreover, predictors for alert adherence were analysed. RESULTS: In phase 1, 552 of 12,197 (4.5%) prescriptions exceeded upper dose limits. In phase 2, initially 559 warnings were triggered (4.8%, p=0.37). Physicians were responsive to one in four warnings mostly adjusting dosages. Thus, the final prescription rate of excessive doses was reduced to 3.6%, with 20% less excessive doses compared with baseline (p<0.001). No new manifest prescription errors were induced. Physicians' alert adherence correlated with patients' age, prescribed drug class, and reason for the alert. CONCLUSION: During the 90-day study, implementation of a highly specific algorithm-based CDSS substantially improved prescribing quality with a high acceptance rate compared with previous studies.

[Ethical and legal aspects of including patients unable to consent in acute therapy studies. Example of a medication study for the treatment of intracerebral hemorrhage--the Heidelberg procedure]. / Ethische und juristische Aspekte beim Einschluss nicht einwilligungsfähiger Patienten in Akuttherapie-Studien. Beispiel einer Arzneimittelstudie zur Behandlung intrazerebraler Blutungen--das Heidelberger Verfahren.

Clinical trials in patients who cannot sign an informed consent are only possible under certain circumstances. The present paper explains the legal prerequisites and ethic rationales, which may allow including patients in such a trial without having signed informed consent. Translation of these prerequisites into practice needs the implementation of special inclusion procedures. These procedures will be explained using the example of the recombinant factor VIIa (rFVIIa) trials for intracerebral hemorrhage.

Calcium balance during calcitriol and paricalcitol administration in healthy humans.

OBJECTIVE: Secondary hyperparathyroidism in hemodialysis patients requires optimal correction of vitamin D deficiency with active vitamin D and analogues. It has been postulated that new vitamin D analogues, i.e. paricalcitol, efficiently suppress parathyroid hormone serum levels (PTH), but do not increase intestinal calcium absorption as much as calcitriol. The effects of calcitriol and paricalcitol on calcium balance can best be characterized under standardized conditions in healthy individuals with normal renal function, because the urinary calcium excretion at steady state corresponds to the net calcium absorption in the gut. METHODS: In a randomized, double-blind, placebo-controlled, 3-way crossover Phase I study in 13 healthy individuals we investigated the changes compared to placebo in PTH and urinary calcium excretion during 6-day treatment periods with paricalcitol (1.5 microg/day) and calcitriol (0.5 microg/day). RESULTS: 24-hour urinary calcium excretion was stable during 6 days of placebo administration. Neither paricalcitol nor calcitriol significantly changed calcium excretion. Urinary creatinine, magnesium and phosphate excretion also remained unchanged over the study periods irrespective of the treatment. However, calcitriol was shown to be effective in reducing iPTH levels during 6 days of treatment (mean reduction 4.03+/-0.69 pmol/l), whereas paricalcitol had no effect. CONCLUSION: Using a dosing ratio of 1:3 for calcitriol:paricalcitol, i.e. the same conversion factor used previously in studies on hemodialysis patients, only calcitriol was able to reduce iPTH levels in healthy individuals. Low-dose calcitriol reduced iPTH levels without raising calcium absorption and without including any hypercalcemia.

Rule-based standardised switching of drugs at the interface between primary and tertiary care.

INTRODUCTION: Changes in drug treatment are frequently mandatory with hospital admission and discharge because hospital drug formularies are generally restricted to about 3000 drugs as compared to the many times this number - 62,000 in Germany - that are commercially available. Without computerised support, the process involved with switching drugs to a corresponding generic or a therapeutic equivalent is time-consuming and error-prone. METHODS: We have developed and tested a standardised interchange algorithm for subsequent implementation into a computerised decision support system that switches drugs to the corresponding generic or a therapeutic equivalent if they are not listed on the hospital drug formulary. RESULTS: The algorithm was retrospectively applied to the medication regimens of 120 patients (774 prescribed drugs containing 886 active ingredients) at their time of admission to surgical wards. Of the prescribed drugs, 52.8% (409/774) were part of the hospital drug formulary, thereby rendering a switch unnecessary. The 365 drugs not listed consisted of 392 active ingredients that were successfully switched to a corresponding generic (84.7%) or a therapeutic equivalent (10.2%). No specific switching procedures were defined for only 2.3% (20/886) of the active ingredients. In these cases, the drugs were either discontinued (4/20) or special drug classes, current diseases or co-medication required manual switching (8/20), or the drugs were continued unchanged and ordered from a wholesaler (8/20). CONCLUSION: Using a standardised interchange algorithm, pre-admission drug regimens can successfully be switched to drugs on a hospital drug formulary. These findings suggest that a computerised decision support system will likely be useful to support this important practice.

Reduction in non-glomerular renal clearance of the caffeine metabolite 1-methylxanthine by probenecid.

OBJECTIVE: Urinary caffeine metabolic ratios used to quantify the activity of numerous drug-metabolizing enzymes are an established component of cocktail approaches for metabolic phenotyping. Because in vitro evidence suggests that 1-methylxanthine (1-MX), a major caffeine metabolite, is actively secreted into urine by organic anion transporters (hOATs), coadministration of renal hOAT inhibitors like probenecid may impair these procedures. METHODS: In a randomized, placebo-controlled, double-blind crossover design, single oral doses of 300 mg caffeine with oral coadministration of placebo or 500 mg probenecid 3 times daily for 2 days were administered to 7 healthy men. The plasma and urine concentrations of caffeine and its major metabolites 1,7-dimethylxanthine (1,7-DMX) and 1-MX were determined by high-performance liquid chromatography. RESULTS: Coadministration of probenecid resulted in a 34% reduction of the renal clearance of 1-MX (mean +/- SD 190 +/- 42 versus 290 +/- 83 ml min(-1), 95% CI on difference 0.2, 200, p = 0.04) with a 41% reduction in its estimated non-glomerular clearance. The renal clearances of caffeine and 1,7-DMX and the area under the plasma concentration-time curves of all substances were not significantly changed. CONCLUSIONS: 1-MX undergoes renal tubular secretion which is substantially reduced by probenecid, possibly due to inhibition of renal hOATs. This inhibition may explain the influence of probenecid on urinary caffeine metabolic ratios and, thus, its impact on the assessment of enzyme activities. It also suggests that 1-MX might serve as a model substrate for the renal tubular transport of organic anions.

[Drugs during pregnancy and breastfeeding: new risk categories--antibiotics as a model]. / Arzneimittel in Schwangerschaft und Stillzeit. Neue Risikokategorien--dargestellt am Beispiel von Antibiotika.

BACKGROUND AND OBJECTIVE: In selecting drugs for treatment during pregnancy and breastfeeding it is essential to be certain of their safety. But categories are lacking that systematically relate the current state of knowledge of individual substances--rather than just drug classes--to each trimester of pregnancy. As such a stratification of risk would be helpful, it was the aim of this study to propose a new and more differentiated classification. METHODS: Internationally available literature and electronic data bases providing details on adverse effects of individual drugs during pregnancy and breastfeeding as well as summaries of product characteristics of the drugs served as comprehensive sources of information. Account was taken of compound-specific data on toxicity during the reproductive and developmental stages, genotoxicity and carcinogenicity (in animals and in-vitro experiments) and drug-specific experience as documented in women during pregnancy and breastfeeding. RESULTS: A new risk classification and appropriate recommendations for clinical management were developed to ensure the safety of drugs given during pregnancy and breastfeeding, taking into account the varying risks during the three trimesters of pregnancy and the perinatal period. Antibiotics were selected as a model for drugs in general and classified according to the new system. CONCLUSION: The proposed new classification of risk makes it possible to select safe agents in the treatment of pregnant and/or breastfeeding women. It is based on the current state of knowledge about a particular substance, also in relationship to the developmental phase of the breastfed child.

Elevated plasma concentrations of lipoprotein(a) in medicated epileptic patients.

Lipoprotein(a) [Lp(a)] has been identified as an independent risk factor for vascular diseases. There are no data on Lp(a) levels in patients on long-term medication with carbamazepine, phenytoin, phenobarbital, or valproate. To investigate the effects of such treatment on Lp(a) levels and common carotid artery intima media thickness we studied 51 epileptic outpatients on long-term antiepileptic medication and 51 age-and sex-matched controls. Lp(a) levels above 45 mg/dl were found in 11 of 50 patients, but in only 4 of 51 controls (P < 0.05). The mean serum concentration of Lp(a) was 33.0+/-7.0 mg/dl in patients and 16.9+/-2.7 mg/dl in controls (P < 0.05). Epileptic patients also had a thicker intima media of the common carotid artery (0.79+/-0.04 mm) than controls (0.69+/-0.02 mm, P < 0.05) as measured by B-mode ultrasonography. Our results suggest an untoward effect of long-term antiepileptic medication on Lp(a) serum concentrations. Elevated Lp(a) levels might be a risk factor for arteriosclerosis in epileptic patients.

[Consideration of drug absorption in customizing drug therapy]. / Berücksichtigung der Arzneimittelabsorption in der Individualisierung der Arzneimitteltherapie.

The rate and extent of drug absorption from the small intestine are related to the release of the active ingredient from a dosage form, its solubility in the liquid phase of gastrointestinal contents, and the transport of the dissolved compound or the intact dosage form from the stomach into the duodenum. With pharmaceutical preparations releasing the active compound within the stomach, and enteric-coated "micro"-formulations (micropellets), gastric emptying is possible during the interdigestive and the digestive period. Potential differences of drug absorption between fasting administration and intake during the digestive period are unpredictable, because they are related to the release characteristics of the dosage form. However, larger enteric-coated preparations like tablets can leave the stomach only with a phase 3 contraction of fasting motility; intake during the digestive period will result in gastric retention of this type of dosage form until all food has left the stomach and fasting motility is restored. Consequently the onset of drug absorption is delayed. This interaction between food and large enteric-coated dosage forms is predictable from pyloric function in relation to the gastric motility. As it occurs regularly, it can be taken into account when prescribing enteric-coated dosage forms. If concomitant intake of food and enteric-coated drugs is unavoidable, but a rapid onset of drug absorption is necessary, micropellets are the dosage form of choice. When the therapeutic effect is insufficient, drug dosage form and timing of drug administration should be checked before prescribing a different active compound.

Heparin-mediated selective release of hepatocyte growth factor in humans.

AIMS: The aim of this investigation was to compare the effects of standard (S) with low molecular weight (LMW) heparin on circulating levels of heparin-binding growth factors (HBGF), known to have angiogenic properties in humans. METHODS: In two consecutive trials 18 healthy male volunteers were studied on three separate occasions, following a placebo-controlled crossover design. Subjects were randomised to receive either S-heparin or LMW heparin or placebo. Heparins were administered either by intravenous (i.v.) or subcutaneous (s.c.) injection and saline placebo by i.v. injection. Serum concentrations of hepatocyte growth factor (HGF), vascular endothelial cell growth factor (VEGF) and basic fibroblast growth factor (bFGF) were measured before and up to 24 h after injection. RESULTS: Administration of i.v. S-or LMW-heparin (50 IU kg(-1) resulted in rapid, highly significant (47 fold for S, 30.9 fold for LMW) increases in HGF serum values, reaching maxima of 10.51+/-1.65 ng ml(-1) (S) and 8.28+/-1.04 ng ml(-1) (LMW), respectively, 10 min after drug application. S.c. injection of S-heparin or LMW heparin resulted in 4.1 and 5.4 fold increases in HGF serum values, respectively. Both agents showed no effects on circulating VEGF or bFGF levels, independent of the route of administration. CONCLUSIONS: Circulating HGF levels were selectively increased in response to pharmacological doses of two, widely used heparin preparations. This may, in part, explain some of the biological effects of heparin separate from its anticoagulant properties. By this mechanism, the systemic administration of heparin may facilitate collateral vessel formation in various clinical settings of tissue ischaemia.

Acute disseminated encephalomyelitis after parenteral therapy with herbal extracts: a report of two cases.

Two patients with acute disseminated encephalomyelitis after repeated injection of extracts from several different plants are described. There was no evidence of prior infection or vaccination. Both patients recovered rapidly after treatment with methylprednisolone. Acute disseminated encephalomyelitis should be considered a rare complication of parenteral therapy with herbal extracts.

Elevated plasma concentrations of homocysteine in antiepileptic drug treatment.

PURPOSE: Homocysteine is an experimental convulsant and an established risk factor in atherosclerosis. A nutritional deficiency of vitamin B6, vitamin B12, or folate leads to increased homocysteine plasma concentrations. During treatment with carbamazepine (CBZ), phenytoin, or phenobarbital, a deficiency in these vitamins is common. The objective of the study was to test the hypothesis that antiepileptic drug (AED) treatment is associated with increased homocysteine plasma concentrations. METHODS: A total of 51 consecutive outpatients of our epilepsy clinic receiving stable, individually adjusted AED treatment and 51 sex- and age-matched controls were enrolled in the study. Concentrations of total homocysteine and vitamin B6 were measured in plasma; vitamin B12 and folate were measured in the serum of fasted subjects. RESULTS: Patients and controls differed significantly in concentrations of folate ( 13.5+/-1.0 vs. 17.4+/-0.8 nM and vitamin B6 (39.7+/-3.4 vs. 66.2+/-7.5 nM), whereas serum concentrations of vitamin B12 were similar. The homocysteine plasma concentration was significantly increased to 14.7+/-3.0 microM in patients compared with controls (9.5+/-0.5 microM; p < 0.05, Wilcoxon rank-sum test). The number of patients with concentrations of >15 microM was significantly higher in the patient group than among controls. The same result was obtained if only patients with CBZ monotherapy were included. Patients with increased homocysteine plasma concentrations had lower folate concentrations. CONCLUSIONS: These data support the hypothesis that prolonged AED treatment may increase plasma concentrations of homocysteine, although the alternative explanation that increased homocysteine plasma concentrations are associated with the disease and not the treatment cannot be completely excluded at the moment.

Relationship between hepatic cytochrome P450 3A content and activity and the disposition of midazolam administered orally.

It was recently shown by others that the clearance of midazolam/kg body weight after iv administration correlates with hepatic cytochrome P450 (CYP or P450) 3A content in liver transplant patients. However, after po administration midazolam undergoes significant first-pass metabolism, with significant intestinal extraction. The relationship between hepatic CYP3A and midazolam disposition after po administration had not previously been investigated. The aim of this study was to compare intraindividually hepatic CYP3A content and activity with the in vivo pharmacokinetics of midazolam (7.5 mg) administered po. For 15 patients scheduled for partial liver resection, the AUC values for the observed time period (AUC0-5hr) and to infinity (AUCinf) and the clearance were determined. In a macroscopically normal area of resected liver tissue, the microsomal CYP3A4 content (nanomoles per nanomole of total P450) was measured by immunoblot analysis and parameters (apparent Vmax, apparent KM, and intrinsic clearance) for the microsomal alpha-hydroxylation of midazolam were determined. Clearance/kg in vivo correlated with the apparent Vmax (r2 = 0.45, p < 0.01) and the CYP3A4 content (r2 = 0.29, p < 0.05). We conclude that interindividual variability in the pharmacokinetics of po administered midazolam is in part determined by interindividual variability in the hepatic microsomal Vmax for the alpha-hydroxylation of midazolam. However, the relationship between the disposition of midazolam administered po and hepatic CYP3A content is weaker than that reported after iv administration, indicating the importance of the contribution of intestinal CYP3A to the in vivo disposition of midazolam administered po.

Treatment of hypertension in patients with pre-eclampsia: a prospective parallel-group study comparing dihydralazine with urapidil.

BACKGROUND: The primary objective of treatment in women with severe hypertension and pre-eclampsia is to prevent complications such as encephalopathy and haemorrhage. In many countries dihydralazine is considered the drug of choice for treating hypertension in pregnancy, because it now has been used safely for about 30 years, and the introduction of a new drug in pregnancy is a difficult task with partially unknown hazards. In some other countries combined alpha- and beta-blockers are also used. Taking into account that some patients with pre-eclampsia do not respond to dihydralazine and the drug has serious side-effects like headache and reflex tachycardia, there is some need for developing alternative treatment strategies using drugs that are more adequate for pregnancy than dihydralazine. METHODS: Urapidil is a post-synaptic alpha 1 adrenoceptor antagonist, which is widely used to control hypertensive crises unrelated to pregnancy. Since it is known that pre-eclampsia is associated with increased sympathetic activity, administration of an alpha 1 adrenoceptor antagonist provides a reasonable therapeutic basis. So far there is only one report describing the i.v. use of urapidil in the treatment of hypertension in pregnancy unresponsive to dihydralazine and one report which describes the oral use of urapidil. In an earlier pilot study we examined the dose range for i.v. application of urapidil necessary for adequate blood pressure control in patients with pre-eclampsia. In the present randomized controlled study 26 white women with pre-eclampsia and hypertension in pregnancy were included. Treatment was not blinded. During the initial period of intensive intravenous treatment all subjects were under constant surveillance by a physician and a nurse. RESULTS: Effective prolonged control of blood pressure (values below 150/100 mmHg) was achieved in all patients of the two groups. In one patient of the dihydralazine group signs of lightheadedness and near syncope were noted. After this side-effect of dihydralazine the patient was treated with urapidil. At the end of the observation period the maternal heart rate in the dihydralazine group was higher than in the urapidil group. CONCLUSIONS: Since urapidil decreased the high blood pressure in patients with pre-eclampsia without serious side-effects urapidil appears preferable superior to dihydralazine. The haemodynamic effects of urapidil were more predictable than those of dihydralazine. The reduction of intracerebral pressure could be an additional advantage of urapidil in the treatment of patients with pre-eclampsia.

Biliary excretion of benzbromarone and its hydroxilated main metabolites in humans.

Hepatic metabolism of the uricosuric drug benzbromarone results in the formation of two hydroxilated main metabolites M1 (1'-hydroxybenzbromarone) and M2 (6-hydroxybenzbromarone). As urinary excretion of benzbromarone and its metabolites is very low, we investigated biliary and plasma concentrations of the parent drug and the metabolites after oral administration of a single 100 mg dose of benzbromarone in 6 patients requiring diagnostic gastroduodenoscopy. Benzbromarone, M1 and M2 were detectable in bile samples 12 hours after drug application. No dehalogenated derivatives (bromobenzarone, benzarone) were present in the bile. 12h, 24h, and 36h plasma concentrations of the parent drug and the main metabolites varied substantially. Our data provide direct evidence of biliary excretion of benzbromarone and its hydroxilated main metabolites 1'-OH-bzbr (M1) and 6-OH-bzbr (M2) and demonstrate the lack of excretion of debrominated products.

Disease-specific noncompliance with drug treatment as a cause of persistent hyperuricemia and gout in anorexia nervosa.

A 49 year old female patient with anorexia nervosa was admitted to the hospital because of treatment-refractory hyperuricemia and gout. Medical history and clinical findings were compatible with primary gout and uric acid nephropathy. The patient stated that she regularly took allopurinol. In the hospital she initially received 300 mg allopurinol daily after breakfast. In order to ensure allopurinol ingestion and absorption the plasma concentrations of both allopurinol and its active metabolite oxipurinol were determined in addition to serum uric acid and further clinical chemistry data. Despite allopurinol treatment no decrease of serum uric acid was observed for three days. Therefore the head nurse was instructed to supervise the intake of allopurinol carefully. During the following days serum uric acid decreased and plasma oxipurinol concentrations rose. On day 9 of treatment serum uric acid fell into the upper normal range. Therefore the patient was allowed to leave the hospital within a few days. However serum uric acid thereafter increased again while plasma oxipurinol declined. Later on it became evident that the patient had vomited self-induced approximately 15 minutes after allopurinol intake. In the meantime her husband had urged her to return home. Starting with day 18 benzbromarone treatment was added. Combined therapy with 400 mg allopurinol and 50 mg benzbromarone daily finally resulted in a serum uric acid concentration of 4.5 mg/dl at discharge from the hospital. About three weeks later the private physician again diagnosed hyperuricemia with serum uric acid values between 10 and 12 mg/dl. Meanwhile the patient needs to be dialysed due to end stage renal disease. Our observations show that self-induced vomiting to prevent effective treatment may be a disease-specific pattern of noncompliance with drug therapy in anorexia nervosa.

D-thyroxine reduces lipoprotein(a) serum concentration in dialysis patients.

Uremia raises lipoprotein(a) (Lp(a)) serum concentration and the risk of arteriosclerosis in dialysis patients. The treatment of high Lp(a) levels is not satisfactory today. The decrease of Lp(a) in hypothyroid patients on L-T4 therapy raised the question of whether dextro-thyroxine (D-thyroxine) reduces not only serum cholesterol, but also Lp(a) serum concentration. In a single-blind placebo-controlled study, the influence of D-thyroxine therapy on Lp(a) serum concentration was evaluated in 30 hemodialysis patients with elevated Lp(a) serum levels. Lp(a) was quantified in parallel by two methods, i.e., rocket immunoelectrophoresis and nephelometry, and apo(a) isoforms were determined by a sensitive immunoblotting technique. Regardless of the apo(a) isoforms, 6 mg/d D-thyroxine reduced elevated Lp(a) levels significantly by 27 +/- 13% in 20 dialysis patients (P < 0.001) compared with 10 control subjects (-9.9 +/- 8.4%). In parallel, D-thyroxine therapy significantly lowered total cholesterol (P < 0.001), LDL cholesterol (P < 0.001), and LDL cholesterol/HDL cholesterol ratio (P < 0.01); raised T4 and T3 serum levels; and suppressed thyroid-stimulating hormone secretion without causing clinical symptoms of hyperthyroidism in any of the patients. D-Thyroxine reduces elevated serum Lp(a) concentration in dialysis patients. The effect in nondialysis patients can be expected but remains to be proven.

[Secondary resistance to coumarin derivatives in a patient with a hypercoagulability syndrome]. / Sekundäre Resistenz gegen Cumarinderivate bei einer Patientin mit Hyperkoagulabilitäts-Syndrom.

HISTORY AND CLINICAL FINDINGS: A 23-year-old woman with deep (leg) vein thrombosis was hospitalised because the Quick value had not decreased despite administration of phenprocoumon. Two years previously she had sustained an anterior wall myocardial infarction and a scar on her right kidney had been an incidental sonographic finding. There was bluish, fine reticular discoloration over the toes of both legs. Physical examination was otherwise unremarkable except for obesity. INVESTIGATIONS: The concentration of creatine kinase was raised to 250 U/l and that of lactate dehydrogenase to 300 U/l. The platelet count was decreased to 75/nl. The level of IgG anti-cardiolipin antibodies was raised (204 U/l) and the test for lupus anticoagulant positive. A biopsy of the skin from a toe revealing livedoid vasculitis, primary antiphospholipid syndrome (PAPS) was diagnosed. TREATMENT AND COURSE: Noncompliance, excessive vitamin K ingestion, drug interaction and malabsorption were excluded as cause of the lacking action of phenprocoumon. Despite anti-coagulation with high-dosage low-molecular heparin and inhibition of platelet aggregation with ticlopidine and finally also immunosuppressive treatment with cyclophosphamide, skin necroses developed on the toes and she had recurrent pulmonary embolisms of which she died. CONCLUSION: Standard treatment of PAPS is effective anti-coagulation with coumarin derivatives. Secondary resistance to coumarin is a rare occurrence: its cause remains unknown.

Fasting and postprandial disposition of R(-)- and S(+)-ibuprofen following oral administration of racemic drug in healthy individuals.

The effects of preceding food intake on the plasma concentrations of R(-)-ibuprofen and the pharmacologically active enantiomer S(+)-ibuprofen were investigated in healthy subjects. A single oral dose of 400 mg racemic ibuprofen was administered either fasting or following a standardized meal. As compared to fasting administration postprandial drug intake resulted in a clear reduction of R(-) and S(+)- ibuprofen plasma concentrations mainly during the initial three hours. The ratio of S(+)/R(-)-ibuprofen postprandially was increased for Cmax and AUC o-tmax as well as for AUC o-infinity. These data are compatible with a meal-induced enhancement of chiral inversion of R(-) to S(+)-ibuprofen. The significant reduction of plasma concentrations of ibuprofen mainly during the initial three hours suggests that the analgesic efficacy is diminished when the drug is taken after a meal. This may to a slight extent be compensated for by a small increase of the metabolic inversion of the R(-)-enantiomer into the active S(+)-form of the drug.

Influence of diet and nutritional status on drug metabolism.

Genetic and environmental factors contribute to a wide inter- and intraindividual variability in drug metabolism. Among the environmental factors that may influence drug metabolism, the diet and nutritional status of the individuals are important determinants. As altered drug-metabolising enzyme activities can influence the intensity and duration of drug action, such factors should be considered in pharmacotherapy. For this reason the effects of dietary energy, protein deficiency, nutritional ingredients, special diet forms and nutrition regimens and malnutritional states must be differentiated. In various pharmacokinetic studies different model drugs metabolised either by oxidative phase I pathways [e.g. phenazone (antipyrine), aminopyrine, phenacetin, theophylline, propranolol, nifedipine] or phase II conjugation reactions [e.g. paracetamol (acetaminophen), oxazepam] were used and from the calculated pharmacokinetic data some information on the involved and affected drug-metabolising enzymes [e.g. cytochrome P450 (CYP) subspecies, glucuronosyltransferases] can be generated. It is well known that smoking, charcoal broiled food or cruciferous vegetables induce the metabolism of many xenobiotics, whereas grapefruit juice increases the oral bioavailability of the high clearance drugs nifedipine, nitrendipine or felodipine by inhibiting their presystemic (intestinal) elimination. Energy deficiency, and especially a low intake of protein, will cause a decrease of about 20 to 40% in phenazone and theophylline clearance and elimination of those drugs can be accelerated by a protein-rich diet. In the same way, protein deficiency induced by either vegetarian food or undernourishment will have the opposite pharmacokinetic consequences. On the basis of some more examples from the literature it is emphasised that the variable influence of the above factors should be taken into account in study participant selection and study design when the pharmacokinetics of a drug must be determined in healthy individuals and/or patients.