Drug interactions in hypertensive patients. Pharmacokinetic, pharmacodynamic and genetic considerations

Antihypertensive treatment has proven benefits, and the number of patients being treated with these drugs is significant. Hypertensive patients may have other medical illnesses for which they receive medications, and interactions between antihypertensive agents and other drugs is likely. Some of these interactions may lead to undesirable effects or even loss of blood pressure control. However, drug interactions can also be beneficial when 2 antihypertensive drugs with different pharmacological actions are prescribed in combination and with a clear therapeutic objective in mind. Clinicians should be aware of the mechanisms and the consequences of the different types of interaction in hypertensive patients, so that a desired pharmacological response can be achieved with the fewest side effects in the patients.     

Metabolic fate of carteolol hydrochloride, (OPC-1085) VIII, a new beta-adrenergic blocking agent. Pharmacokinetic studies of carteolol in man.

The pharmacokinetics of 5-(3-tert.-butylamino-2-hydroxy)-propoxy-3,4-dihydrocarbostyril hydrochloride (carteolol hydrochloride, OPC-1085) have been investigated in man following single or repetitive oral administration. The plasma half-lives. The plasma half-lives of carteolol at single doses of 10, 15 and 30 mg were 5.4, 5.5 and 5.0 h, respectively. The amounts of carteolol excreted into urine within 24 h at the same dose levels accounted for 64, 70 and 76% of the respective doses. The half-lives obtained by the Sigmaminus method were 5.6, 5.6 and 5.4 h, respectively, being essentially consistent with the aforementioned plasma half-lives of carteolol after administration at 15 mg daily for 7 successive days were determined to be 5.54 h on the 1st day and 6.91 h on the 7th day, displaying the increase in half-life value with the repetitive dosing. While, the predicted value determined using the experimental value on the 1st day agreed with the experimental value on the 7th day. Furthermore, the amounts of carteolol excreted in the urine were not significantly different between the 1st and 7th days. The 7-day repetitive administration with carteolol brought about the steady state of plasma levels. It was concluded from these results that carteolol has little ability to accumulate in man.     

Pharmacokinetic and pharmacodynamic interactions of mefloquine and quinine

This study was carried out to investigate the pharmacokinetic and pharmacodynamic interactions between two antimalarial drugs, mefloquine and quinine. A randomized, comparative, three-way crossover study was performed in seven healthy male Thais after the administration of three drug regimens on three occasions i.e., a single oral dose of quinine sulfate (600 mg), mefloquine (750 mg) alone, or the combination of mefloquine (750 mg) and quinine (600 mg given 24 h after mefloquine). QTc interval was significantly prolonged in subjects following the combination regimen (at 2.5, 3, 4, 6, 8, 12, 18, 24 h after the quinine dose) but no abnormal clinical signs or symptoms were found. There were no significant changes in vital signs or routine laboratory values in any of the subjects. The pharmacokinetics of mefloquine and quinine were influenced by the presence of the other drug. Greater blood schizonticidal activities were collected from the sera of subjects on the combination regimen than from the sera of subjects the quinine or mefloquine regimens. The minimum inhibitory concentrations (MICs) of the equivalent concentrations (Eqs) of quinine or mefloquine, which completely inhibited the growth of the K1 strain of Plasmodium falciparum in vitro (MICs of quinine Eq and mefloquine Eq) were significantly lower in the sera of subjects on the combination regimens, than in the sera of subjects on mefloquine or quinine alone [MICs of quinine Eq: 41.2 (21.25-73.5) vs. 135 (118-150) ng/ml; MICs of mefloquine Eq: 18.2 (17-19.2) vs. 25.2 (24.4-26.8) ng/ml].     

Pharmacokinetic and pharmacodynamic interactions of morin and cyclosporin

Morin is a flavonoid present in mulberry and herbs. We have reported that morin exerted anti-inflammatory activity on the activated macrophages. Cyclosporin (CsA) is a potent immunosuppressive agent with narrow therapeutic range, which is widely used for the treatments of autoimmune diseases and transplantation rejection. This study aimed to measure the effects of morin on the disposition of CsA in lymphoid and non-lymphoid tissues, and on the functions of immune cells in mice. CsA (Neoral, 10 mg/kg) was orally administered with and without a concomitant dose of morin (0, 50, 100, 200 mg/kg) to mice once daily for 2 weeks. CsA concentrations in blood, liver, kidney, and spleen were determined by a specific monoclonal fluorescence polarization immunoassay. The decreased levels of CsA in tissues were found well correlated to increased doses of morin. The coadministration of 200 mg/kg morin significantly decreased CsA in blood, liver, kidney, and spleen by 33%, 17%, 38%, and 45%, respectively. On the other hand, coadministration of morin decreased dramatically the nitric oxide production by the activated macrophages when compared to CsA treatment alone. Moreover, morin maintained the level of CsA-suppressed T helper 1 (Th1) type cytokine, although the CsA concentration in spleen was markedly reduced. In conclusion, morin coadministration profoundly reduced CsA concentration but did not significantly alter the CsA-suppressed Th1 immune response in mice.     

Pharmacokinetic and pharmacodynamic interactions of propafenone and cimetidine

The pharmacokinetics and pharmacodynamics of the extensively metabolized antiarrhythmic agent propafenone were assessed alone and during concomitant administration of cimetidine. Twelve healthy subjects were given successively the following treatments: propafenone 225 mg q8h plus cimetidine placebo; cimetidine 400 mg q8h plus propafenone placebo; and propafenone 225 mg plus cimetidine 400 mg q8h. After a minimum of 5 days on each regimen, plasma drug concentrations and electrocardiogram conduction intervals were measured during a drug washout period. The maximum concentration of propafenone in plasma was 993 +/- 532 ng/mL when propafenone was given alone compared with 1230 +/- 591 ng/mL when propafenone was given with cimetidine (P = .0622). Differences in tmax, t1/2, and Cp ss did not approach statistical significance when propafenone alone was compared with propafenone plus cimetidine. When compared with cimetidine, propafenone significantly increased the PR interval from 161 +/- 5 msec to 192 +/- 6 msec (P less than .01) and the QRS duration from 89 +/- 3 msec to 98 +/- 4 msec (P less than .01). Combination therapy caused a modest additional increase in QRS duration to 103 +/- 3 msec (P less than .01). In conclusion, cimetidine caused small changes in propafenone pharmacokinetics and pharmacodynamics; but these changes are unlikely to be clinically important.     

Pharmacokinetic and pharmacodynamic interactions between caffeine and diazepam

The pharmacokinetic and dynamic interactions of caffeine and diazepam after single doses were investigated in six young healthy adults. Subjects received 6 mg/kg of caffeine, 0.3 mg/kg of diazepam, and their combination at 2-week intervals according to a Latin square design and a double-blind procedure. Subjects had blood samples withdrawn at 0, 5, 10, 20, 30, 45, 60 minutes and every 30 minutes thereafter until 210 minutes after treatment. A battery of behavioral tests were administered before treatment and after each blood sampling, starting with the 20-minute period. The coadministration of caffeine with diazepam resulted in a 22% reduction in diazepam plasma levels. Caffeine produced hand tremors and diazepam produced sedation and impaired memory and cognition. The two drugs did not antagonize the effects of each other except in the symbol cancellation task. There were significant correlations between the caffeine and diazepam plasma levels and performance on several tasks and evidence for the development of acute tolerance to both drugs.     

No pharmacokinetic but pharmacodynamic interactions between cisapride and bromperidol or haloperidol.

Pharmacokinetic and pharmacodynamic interactions between the gastrokinetic drug cisapride and the antipsychotic drugs bromperidol and haloperidol were studied in 29 schizophrenic inpatients. Fourteen patients were taking bromperidol (12-24 mg/d), and 15 were taking haloperidol (12-36 mg/d). Cisapride 10 mg/d was coadministered for 1 week, and blood sampling was performed before cisapride treatment, 1 week after starting cisapride treatment, and I week after stopping cisapride treatment. On the same days as the blood sampling, psychotic symptoms and side effects were evaluated using the Brief Psychiatric Rating Scale (BPRS) and the Udvalg for Kliniske Unders?gelser (UKU) side effect rating scale (UKU), respectively. Plasma concentrations of bromperidol, haloperidol, and their reduced metabolites were measured by high-performance liquid chromatography. The mean BPRS scores after adding cisapride were significantly higher than those before cisapride (p<0.01) and after stopping cisapride (p<0.001) in the haloperidol group in this uncontrolled study. A similar tendency was observed in the bromperidol group, although it did not reach statistical significance (p = 0.08). Cisapride coadministration caused no significant changes in the mean plasma concentrations of bromperidol, haloperidol, and their reduced metabolites or in the mean UKU score. The present study suggests that there is no significant pharmacokinetic interaction between cisapride and bromperidol or haloperidol, but cisapride appears to deteriorate psychotic symptoms by a pharmacodynamic interaction in schizophrenic patients treated with haloperidol.     

Tardive dyskinesia during and following treatment with haloperidol,haloperidol + biperiden,thioridazine, and clozapine

In a cross-over trial 16 elderly psychiatric patients with tardive dyskinesia were treated with thioridazine (median dose, 267.5 mg/day) for three months, followed by haloperidol (5.25 mg/day), haloperidol (5.25 mg/day) + biperiden (6 mg/day), thioridazine (267.5 mg/day), and clozapine (62.5 mg/day, only 7 patients), all for periods of 4 weeks with 4-week drug-free intervals. The tardive dyskinesia syndrome and the parkinsonism were evaluated blind according to a self-constructed rating scale and a modified Webster scale from weekly video-tape recordings. At the end of the treatment periods the hyperkinesia score was lower during haloperidol than during either thioridazine for 3 months (total score, 2.2 vs. 3.2, P<0.05), thioridazine for 4 weeks (total score, 2.2 vs. 4.8, P<0.02), or haloperidol + biperiden (score, 2.2 vs. 6.2, P<0.01). Clozapine had no significant antihyperkinetic effect, but in one patient it exerted a clear antiparkinsonian effect. After withdrawal of the initial thioridazine treatment, the hyperkinesia score was lower than after the subsequent haloperidol treatment (6.5 vs. 9.0, P<0.01), but after the second thioridazine period the hyperkinesia was of the same magnitude as after the preceding haloperidol periods. Biperiden increased the tardive dyskinesia syndrome during treatment, but did not significantly influence the syndrome after withdrawal of the treatment.It is concluded that (1) haloperidol (a strong antidopaminergic neuroleptic) has a more pronounced antihyperkinetic effect than thioridazine and clozapine (weaker antidopaminergic neuroleptics); (2) haloperidol might have a greater tendency to induce tardive dyskinesia than thioridazine; (3) administration of anticholinergics concomitant with neuroleptic drugs antagonizes the antihyperkinetic effect of haloperidol, but may not influence the intensity of tardive dyskinesia after withdrawal of the treatment.     

Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol

1 Interaction between alcohol and bretazenil (a benzodiazepine partial agonist in animals) was studied with diazepam as a comparator in a randomized, double-blind, placebo controlled six-way cross over experiment in 12 healthy volunteers, aged 19−26 years.
2 Bretazenil (0.5  mg), diazepam (10  mg) and matching placebos were given as single oral doses after intravenous infusion of alcohol to a steady target-blood concentration of 0.5  g l⁻¹ or a control infusion of 5% w/v glucose at 1 week intervals.
3 CNS effects were evaluated between 0 and 3.5  h after drug administration by smooth pursuit and saccadic eye movements, adaptive tracking, body sway, digit symbol substitution test and visual analogue scales.
4 Compared with placebo all treatments caused significant decrements in performance. Overall, the following sequence was found for the magnitude of treatment effects: bretazenil+alcohol>diazepam+alcohol≥bretazenil> diazepam>alcohol>placebo.
5 There were no consistent indications for synergistic, supra-additive pharmacodynamic interactions between alcohol and bretazenil or diazepam.
6 Bretazenil with or without alcohol, and diazepam+alcohol had marked effects. Because subjects were often too sedated to perform the adaptive tracking test and the eye movement tests adequately, ceiling effects may have affected the outcome of these tests.
7 No significant pharmacokinetic interactions were found.
8 Contrary to the results in animals, there were no indications for a dissociation of the sedative and anxiolytic effects of bretazenil in man.     

Pharmacokinetic and pharmacodynamic studies following the intravenous and oral administration of the antiparkinsonian drug biperiden to normal subjects

Summary The pharmacokinetics and pharmacodynamics (changes in pupil size and salivary flow) of biperiden following a single oral and intravenous dose were investigated in six normal subjects.After the injection plasma concentrations declined biphasically, with half-times of 1.5 h for the rapid phase and 24 h for the terminal phase. Clearance and apparent volume of distribution were high (12 ml·min^–1·kg^–1 and 24 l·kg^–1 respectively). Absorption was rapid but the systemic availability was incomplete (33%), probably due to first-pass metabolism.Central nervous system (CNS) adverse effects and changes in pupil size were observed after both routes of administration while salivary flow was affected only by the injection.     

Pharmacokinetic and pharmacodynamic interactions of diazepam with different alcoholic beverages

Summary Twenty paid healthy students ingested diazepam 10 mg 30 min after the administration of ethanol 0.8 g/kg. The alcoholic beverage used was varied in randomized double-blind experiments, which were repeated at one-month intervals. Psychomotor performance, plasma diazepam, and alcohol concentration in breath were measured 30, 60, 90 min and 2, 3, 4, 6 and 24 h after the ingestion of diazepam. Beer and white wine elevated the plasma level of diazepam and the effect lasted for up to 2 h. Whisky elevated the diazepam level for 90 min. Red wine did not affect it significantly. The alcohol-diazepam combination impaired tracking skills and oculomotor co-ordination and enhanced nystagmus, more than diazepam alone. Red wine produced a breath alcohol concentration higher than after white wine. More nystagmus was recorded after red wine and diazepam, although white wine led to a higher plasma diazepam concentration. It appears that simultaneous ingestion of alcohol and diazepam accelerates the absorption of diazepam. This pharmacokinetic alteration may not contribute much to the combined psychomotor effects of diazepam and alcohol, which were mainly due to pharmacodynamic interaction at receptor level.     

Pharmacokinetic and pharmacodynamic drug interactions in the treatment of attention-deficit hyperactivity disorder.

The psychostimulants methylphenidate, amphetamine and pemoline are among the most common medications used today in child and adolescent psychiatry for the treatment of patients with attention-deficit hyperactivity disorder. Frequently, these medications are used in combination with other medications on a short or long term basis. The present review examines psychostimulant pharmacology, summarises reported drug-drug interactions and explores underlying pharmacokinetic and pharmacodynamic considerations for interactions. A computerised search was undertaken using Medline (1966 to 2000) and Current Contents to provide the literature base for reports of drug-drug interactions involving psychostimulants. These leads were further cross-referenced for completeness of the survey. Methylphenidate appears to be more often implicated in pharmacokinetic interactions suggestive of possible metabolic inhibition, although the mechanisms still remain unclear. Amphetamine was more often involved in apparent pharmacodynamic interactions and could potentially be influenced by medications affecting cytochrome P450 (CYP) 2D6. No published reports of drug interactions involving pemoline were found. The alpha2-adrenergic agonists clonidine and guanfacine have been implicated in several interactions. Perhaps best documented is their antagonism by tricyclic antidepressants and phenothiazines. In additional, concurrent beta-blocker use, or abrupt discontinuation, can lead to hypertensive response. Although there are few published well-controlled interaction studies with psychostimulants and alpha2-adrenergic agonists, it appears that these agents may be safely coadministered. The interactions of monoamine oxidase inhibitors with psychostimulants represent one of the few strict contraindications.     

Olanzapine. Pharmacokinetic and pharmacodynamic profile.

Multicentre trials in patients with schizophrenia confirm that olanzapine is a novel antipsychotic agent with broad efficacy, eliciting a response in both the positive and negative symptoms of schizophrenia. Compared with traditional antipsychotic agents, olanzapine causes a lower incidence of extrapyramidal symptoms and minimal perturbation of prolactin levels. Generally, olanzapine is well tolerated. The pharmacokinetics of olanzapine are linear and dose-proportional within the approved dosage range. Its mean half-life in healthy individuals was 33 hours, ranging from 21 to 54 hours. The mean apparent plasma clearance was 26 L/h, ranging from 12 to 47 L/h. Smokers and men have a higher clearance of olanzapine than women and nonsmokers. After administering [14C]olanzapine, approximately 60% of the radioactivity was excreted in urine and 30% in faeces. Olanzapine is predominantly bound to albumin (90%) and alpha 1-acid glycoprotein (77%). Olanzapine is metabolised to its 10- and 4'-N-glucuronides, 4'-N-desmethylolanzapine [cytochrome P450 (CYP) 1A2] and olanzapine N-oxide (flavin mono-oxygenase 3). Metabolism to 2-hydroxymethylolanzapine via CYP2D6 is a minor pathway. The 10-N-glucuronide is the most abundant metabolite, but formation of 4'-N-desmethylolanzapine is correlated with the clearance of olanzapine. Olanzapine does not inhibit CYP isozymes. No clinically significant metabolic interactions were found between olanzapine and diazepam, alcohol (ethanol), imipramine, R/S-warfarin, aminophylline, biperiden, lithium or fluoxetine. Fluvoxamine, an inhibitor of CYP1A2, increases plasma concentrations of olanzapine; inducers of CYP1A2, including tobacco smoke and carbamazepine, decrease olanzapine concentrations. Orthostatic changes were observed when olanzapine and diazepam or alcohol were coadministered. Pharmacodynamic interactions occurred between olanzapine and alcohol, and olanzapine and imipramine, implying that patients should avoid operating hazardous equipment or driving an automobile while experiencing the short term effects of the combinations. Individual factors with the largest impact on olanzapine pharmacokinetics are gender and smoking status. The plasma clearance of olanzapine generally varies over a 4-fold range, but the variability in the clearance and concentration of olanzapine does not appear to be associated with the severity or duration of adverse effects or the degree of efficacy. Thus, dosage adjustments appear unnecessary for these individual factors. However, dosage modification should be considered for patients characterised by a combination of factors associated with decreased oxidative metabolism, for example, debilitated or elderly women who are nonsmokers.     

Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam

This review was conducted to identify the current data on drug interactions with alprazolam, midazolam, and triazolam to guide practitioners in the use of these drugs. The Medline electronic database from 1966 through 1998 was used to identify clinical studies of the pharmacokinetic effect of drugs on these three benzodiazepines. Of a total of 491 literature reports identified, 59 prospective studies met our selection criteria. The pharmacokinetic parameters of AUC, Cmax, t1/2, and tmax were evaluated for changes following an interaction. To allow comparison between studies, changes in the parameters were normalized relative to the control values. Pharmacodynamic effects and measures, when reported in the original studies as statistically significant, were classified as a strong interaction, and when the interaction was present but not statistically significant, they were classified as mild in this review. As a result, clinically significant drug interactions were noted for all three benzodiazepines, although it is clear that statistically significant pharmacokinetic changes do not always translate into clinically significant pharmacodynamic consequences. All three benzodiazepines were susceptible to drug interactions, but oral dosing of midazolam and triazolam resulted in greater alterations in the pharmacokinetic parameters than alprazolam due to their larger presystemic extraction. Ketoconazole and itraconazole were found to be the most potent metabolic inhibitors that prolonged the duration of or intensified the magnitude of the dynamic response produced by the three benzodiazepines. Rifampin, carbamazepine, and phenytoin were noted to be potent metabolic inducers, and their treatments result in loss of benzodiazepine therapeutic efficacy. In conclusion, potent metabolic inhibitors and inducers can either significantly prolong or diminish the dynamic effects of benzodiazepines via their influence on the pharmacokinetics of benzodiazepines.     

Pharmacokinetic and pharmacodynamic interactions between omeprazole and amoxycillin in Helicobacter pylori-positive healthy subjects.

BACKGROUND: Omeprazole with amoxycillin has been used to treat Helicobacter pylori infection. It was speculated that omeprazole- induced hypoacidity enhances the antibacterial activity of amoxycillin. Limited information exists about intragastric pH and bioavailability of amoxycillin during combination therapy. No data are available about possible effects of the antibiotic on the pharmacokinetics and pharmacodynamics of omeprazole. METHODS: The study was performed in a three-way cross-over double-blind design. After a run-in period on placebo with a baseline intragastric pH-metry, 24 H. pylori-positive healthy subjects were randomly dosed with amoxycillin 750 mg b.d. + placebo, amoxycillin 750 mg b.d. + omeprazole 40 mg b.d. and omeprazole 40 mg b.d. + placebo for 5 days. On the last day of each regimen intragastric pH-metries were performed, and blood samples taken for omeprazole and amoxycillin serum profiles. RESULTS: Amoxycillin monotherapy had no acid-inhibiting effect. Median pH during combined dosing was significantly lower, compared to omeprazole monotherapy (P < 0.01). Mean serum concentrations of omeprazole and amoxycillin given alone or in combination were not different. CONCLUSIONS: High-dose omeprazole does not alter the pharmacokinetics of amoxycillin. The significantly lower intragastric pH during combination therapy might be due to the H. pylori-suppressive effect of this treatment.     

Pharmacokinetic and pharmacodynamic interactions between dehydroepiandrosterone and prednisolone in the rat

The effects of multiple-dosing with dehydroepiandrosterone sulfate (DHEA-SO4) on the pharmacokinetics and pharmacodynamics of prednisolone were examined. Prednisolone (25 mg/kg i.v.) was administered to male and female Sprague-Dawley rats (250-350 g) alone and following DHEA-SO4 (4 mg/kg i.v., every 8 h for 4 days). Male control rats cleared prednisolone faster [3.68 +/- 1.30 (males) vs 1.01 +/- 0.7 l/h/kg; p < 0.05] and had larger Vss (1.38 +/- 0.459 vs 0.394 +/- 0.500 l/kg; p < 0.05) than females both due largely to lesser plasma protein binding. Prednisolone clearance and Vss were not altered by DHEA-SO4 in males or females. The net effect of prednisolone on basophils and plasma corticosterone did not differ with gender. DHEA-SO4 had no effect on plasma corticosterone and did not alter prednisolone action. DHEA-SO4 inhibited basophil trafficking in males, but to a lesser extent than prednisolone, and antagonized the effect of prednisolone on basophil trafficking in both sexes. The steroid-sparing effect observed with DHEA clinically may not be due to an alteration of corticosteroid pharmacokinetics but partly to its ability to affect immune functions.     

Pharmacokinetic and pharmacodynamic interactions between almorexant,a dual orexin receptor antagonist,and desipramine

Almorexant is a dual orexin receptor antagonist (DORA) with sleep-enabling effects in humans. Insomnia is often associated with mental health problems, including depression. Hence, potential interactions with antidepressants deserve attention. Desipramine was selected as a model drug because it is mainly metabolized by CYP2D6, which is inhibited by almorexant in vitro. A single-center, randomized, placebo-controlled, two-way crossover study in 20 healthy male subjects was conducted to evaluate the pharmacokinetic and pharmacodynamic interactions between almorexant and desipramine. Almorexant 200 mg or matching placebo (double-blind) was administered orally once daily in the morning for 10 days, and a single oral dose of 50 mg desipramine (open-label) was administered on Day 5. Almorexant increased the exposure to desipramine 3.7-fold, suggesting that almorexant is a moderate inhibitor of desipramine metabolism through inhibition of CYP2D6. Conversely, desipramine showed no relevant effects on the pharmacokinetics of almorexant. Pharmacodynamic evaluations indicated that almorexant alone reduced visuomotor coordination, postural stability, and alertness, and slightly increased calmness. Desipramine induced a reduction in subjective alertness and an increase in pupil/iris ratio. Despite the increase in exposure to desipramine, almorexant and desipramine in combination showed the same pharmacodynamic profile as almorexant alone, except for prolonging reduced alertness and preventing the miotic effect of almorexant. Co-administration also prolonged the mydriatic effect of desipramine. Overall, repeated administration of almorexant alone or with single-dose desipramine was well tolerated. The lack of a relevant interaction with antidepressants, if confirmed for other DORAs, would be a key feature for a safer class of hypnotics.     

Pharmacokinetic and pharmacodynamic interactions of oral midazolam with ketoconazole, fluoxetine, fluvoxamine, and nefazodone

The objective of this study was to investigate pharmacokinetic and pharmacodynamic interactions between midazolam and fluoxetine, fluvoxamine, nefazodone, and ketoconazole. Forty healthy subjects were randomized to receive one of the four study drugs for 12 days in a parallel study design: fluoxetine 60 mg per day for 5 days, followed by 20 mg per day for 7 days; fluvoxamine titrated to a daily dose of 200 mg; nefazodone titrated to a daily dose of 400 mg; or ketoconazole 200 mg per day. All 40 subjects received oral midazolam solution before and after the 12-day study drug regimen. Blood samples for determination of midazolam concentrations were drawn for 24 hours after each midazolam dose and used for the calculation of pharmacokinetic parameters. The effects of the study drugs on midazolam pharmacodynamics were assessed using the symbol digit modalities test (SDMT). The mean area under the curve (AUC) for midazolam was increased 771.9% by ketoconazole and 444.0% by nefazodone administration. However, there was no significant change in midazolam AUC as a result of fluoxetine (13.4% decrease) and a statistical trend for fluvoxamine (66.1% increase) administration. Pharmacodynamic data are consistent with pharmacokinetic data indicating that nefazodone and ketoconazole resulted in significant increases in midazolam-related cognition impairment. The significant impairment in subjects' cognitive function reflects the changes in midazolam clearance after treatment with ketoconazole and nefazodone. These results suggest that caution with the use of midazolam is warranted with potent CYP3A4 inhibitors.     

Pharmacokinetic and pharmacodynamic interactions of aspirin with warfarin in beagle dogs

1.?Warfarin and aspirin are widely used in a wide spectrum of thromboembolic and atherothrombotic diseases. Despite the potential efficacy of warfarin–aspirin therapy, the safety and side effect of combined therapy remains unclear.

2.?The aim of this study was to investigate the pharmacokinetic and pharmacodynamic interactions between warfarin and aspirin in beagles after single and multiple doses.

3.?Coadministration of aspirin had no significant effects on the area under the plasma concentration time curve (AUC_0–t) and maximum plasma concentration (C_max) of R- and S-warfarin after a single dose of warfarin, but significantly increase the AUC_0–t and C_max and dramatically decrease the clearance (CL) of R- and S-warfarin after multiple dose of warfarin. Accordingly, there was a slight increase in the AUEC_0–t and E_max of activated partial thromboplastin time (aPTT), prothrombin time (PT) and international normalized ratio (INR) after multiple dose of warfarin.

4.?Coadministration of warfarin had no markedly effects on the AUC_0–t and C_max of aspirin and its metabolite salicylic acid after single or multiple dose of aspirin. Meanwhile, the AUEC_0–t and E_max of inhibition of platelet aggregation (IPA) were not significantly affected by warfarin.

5.?Our animal study indicated that coadministration of aspirin with warfarin can cause significant pharmacokinetic and pharmacodynamic drug–drug interactions in beagles. However, more studies are urgently needed to assess related information of warfarin–aspirin drug interactions in healthy volunteers or patients.     

Pharmacokinetic and pharmacodynamic interactions between the novel calcium sensitiser levosimendan and warfarin

OBJECTIVE: To study the effects of possible interactions between levosimendan and warfarin on pharmacokinetics and pharmacodynamics. Furthermore, the effects of levosimendan on blood coagulation were investigated. METHODS: Open, randomised cross-over design with two treatment phases was used. During one phase, levosimendan (0.5 mg four times daily) was given orally to ten healthy subjects for 9 days. On the fourth treatment day with levosimendan, a single oral dose of warfarin (25 mg) was given. Pharmacokinetic parameters of levosimendan from the third and fourth treatment days were compared with each other. During the other treatment phase the subjects received only a single dose of warfarin. Pharmacokinetic parameters of warfarin alone were compared with those determined after concomitant administration of levosimendan. Changes in blood coagulation parameters were evaluated after levosimendan and warfarin alone and after concomitant administration. RESULTS: Warfarin did not change the pharmacokinetics of levosimendan. The distribution volume of warfarin was higher and elimination half-life shorter after concomitant levosimendan administration than after warfarin alone. However, concomitant levosimendan administration did not potentiate the effects of warfarin on blood coagulation assessed using activated partial thromboplastin time (APTT) and thromboplastin time (TT-SPA). Levosimendan alone for 3 days did not change APTT or TT-SPA values. There were no changes in the protein binding of levosimendan or warfarin upon concomitant administration. Continuous treatment with oral levosimendan caused headache, which was probably due to cerebral vasodilation. CONCLUSIONS: Concomitant levosimendan administration did not potentiate the effect of warfarin on blood coagulation after a single dose. Levosimendan itself had no effects on blood coagulation.