Quantification and mechanism of the fluoxetine and tricyclic antidepressant interaction.

Clinical reports of concurrent use of fluoxetine and tricyclic antidepressant agents suggest that tricyclic concentrations increase upon coadministration with fluoxetine. This study was conducted to confirm the clinical reports, to quantify the degree of change in tricyclic kinetics, and to establish the mechanism of interaction. Twelve male subjects were given 50 mg desipramine (six subjects) or 50 mg imipramine (six subjects) on three occasions: alone, after a 60 mg dose of fluoxetine, and after eight daily 60 mg doses of fluoxetine. Fluoxetine significantly reduced oral clearance of both imipramine and desipramine as much as tenfold and prolonged half-life as much as fourfold. Desipramine oral clearance values were 289, 112, and 27 L/hr alone, after a single fluoxetine dose, and after multiple fluoxetine doses, respectively. Correspondingly, imipramine oral clearance values were 181, 87, and 51 L/hr. These kinetic changes resulted in significantly higher plasma tricyclic concentrations after fluoxetine administration. The amount of parent drug excreted unchanged in urine increased and imipramine or desipramine clearance to their respective 2-hydroxy metabolites decreased. Metabolic conversion of imipramine to desipramine appeared to be unaffected. The findings indicate that fluoxetine causes an inhibition of tricyclic 2-hydroxylation and may decrease first-pass and systemic metabolism. When imipramine or desipramine are to be coadministered with fluoxetine, a lower dosage may be needed to maintain steady-state concentrations and to avoid undesirable side effects caused by excessive tricyclic concentrations.

Fluoxetine disposition and elimination in cirrhosis.

Fluoxetine is a specific and potent inhibitor of presynaptic serotonin reuptake and has been shown to be a clinically effective antidepressant. Elimination of the drug depends primarily on hepatic metabolism, with formation of a pharmacologically active demethylated product, norfluoxetine. The present study assesses for the first time the effect of chronic liver disease on these processes. Our data show that in stable alcoholic cirrhosis, the elimination of fluoxetine is significantly reduced. The mean t1/2 was 6.6 vs. 2.2 days and plasma clearance was 4.2 vs. 9.6 ml/min/kg for patients with cirrhosis vs. normal volunteers, respectively. In addition, the formation of norfluoxetine was decreased and its clearance was also reduced. Thus, at steady state both fluoxetine and norfluoxetine concentrations will be higher in patients with cirrhosis, unless the dosage is reduced. Conventional liver tests and indocyanine green clearance in cirrhosis did not correlate in a predictive manner with individual patients' elimination of fluoxetine.

Absorption studies of the H2-blocker nizatidine.

The absolute and relative bioavailability of nizatidine, an H2-blocker, was studied in healthy male volunteers. The absolute oral bioavailability, relative to that after intravenous administration, was 98% +/- 14%. The bioavailability of single and multiple oral doses of 150 mg nizatidine was unaffected by concurrent food ingestion; nizatidine may be administered either with or without food. The relative bioavailability of nizatidine was compared when given simultaneously with placebo or Gelusil, 30 minutes after propantheline, or 60 minutes before activated charcoal. Gelusil reduced the amount of nizatidine absorbed by about 10%, charcoal reduced it by about 30%, and propantheline did not affect it.

Nizatidine disposition in subjects with normal and impaired renal function.

To test the hypothesis that renal insufficiency alters nizatidine disposition, we determined the pharmacokinetics of nizatidine and its major metabolite after a single oral dose in normal volunteers and patients with various degrees of renal dysfunction, after a single intravenous dose in normal volunteers and patients with severe renal failure and during hemodialysis. After intravenous administration the elimination half-life increased from 1.5 +/- 0.2 hours in normal volunteers to 6.9 +/- 3.3 hours in patients with renal failure. The plasma clearance decreased from 0.59 +/- 0.07 L/kg/hr in normal volunteers to 0.14 +/- 0.02 L/kg/hr in patients with renal failure. Nizatidine bioavailability was nearly 100% in normal volunteers but decreased to 75% in patients with renal failure. The volume of distribution was 1.3 +/- 0.1 L/kg in normal volunteers and was not different in patients with renal failure. Nizatidine protein binding was about 30% in normal and uremic plasma. The drug was not substantially removed by hemodialysis. Patients with creatinine clearances less than 50 ml/min/1.73 m2 should receive 150 mg nizatidine once each evening. Patients with creatinine clearances less than 20 ml/min/1.73 m2 should receive 150 mg nizatidine every other night.

The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam.

To determine the effect of fluoxetine on diazepam's pharmacokinetic and psychomotor responses, single oral doses of 10 mg diazepam were administered to six normal subjects on three occasions, either alone or in combination with 60 mg fluoxetine. Diazepam was given alone, after a single dose of fluoxetine, and after eight daily doses of fluoxetine. Psychometric data showed that fluoxetine had no significant effect on the psychomotor responses to diazepam. However, the pharmacokinetic data indicated a change in diazepam disposition after fluoxetine administration. Diazepam AUC was larger, the half-life was longer, and the plasma clearance was lower after fluoxetine administration, suggesting that fluoxetine inhibited the metabolism of diazepam. The reduced formation of an active metabolite, N-desmethyldiazepam, also suggested that fluoxetine inhibited diazepam's metabolism. The clinical implications of this pharmacokinetic drug-drug interaction are minor because psychomotor responses were unaffected and offsetting changes in the kinetics of diazepam and its metabolite occurred. Dosage modification of either fluoxetine or diazepam is unlikely to be necessary.

The effect of sertraline on the pharmacokinetics of desipramine and imipramine.

OBJECTIVE: To examine the pharmacokinetic interaction between the selective serotonin reuptake inhibitor sertraline and the tricyclic antidepressants desipramine or imipramine in 12 healthy male subjects. METHODS: Participants received a 50 mg single dose of either desipramine or imipramine under three conditions: alone, after a single 150 mg dose of sertraline, and after the eighth daily 150 mg dose of sertraline. Plasma samples were analyzed for desipramine or imipramine concentration by HPLC with electrochemical detection, and pharmacokinetics were determined with use of noncompartmental analysis of individual data. RESULTS: Multiple-dose, but not single-dose, treatment with sertraline significantly reduced apparent plasma clearance (CL/F) and prolonged the half-life of desipramine relative to baseline. These changes resulted in higher plasma desipramine concentrations, as indicated by a significant increase in maximum plasma concentration (Cmax) and area under the plasma concentration-time curve extrapolated to infinity [AUC(0-infinity)] (22% and 54%, respectively). Both single- and multiple-dose treatment with sertraline significantly reduced the CL/F of imipramine. This effect was stronger after multiple predoses of sertraline, when imipramine Cmax and AUC(0-infinity) were increased by 39% and 68%, respectively. These treatment effects were consistent between individuals. CONCLUSIONS: This pharmacokinetic interaction is likely the result of an inhibition of CYP2D6 tricyclic metabolism by sertraline. When a tricyclic antidepressant, such as desipramine or imipramine, is coadministered with sertraline, lower dosages of the tricyclic agents may be necessary to prevent elevated tricyclic levels.

Intravenous nizatidine kinetics and acid suppression.

The effectiveness of intravenous nizatidine in suppressing gastric acid secretion was evaluated by different methods of inducing secretion in two single-blind studies. In study 1, seven subjects were given single, 20-min intravenous infusions of nizatidine (6.25, 25, 75, 150, or 250 mg) before modified sham feeding (MSF). Gastric acid suppression after nizatidine was contrasted with that after placebo and MSF. All doses of nizatidine reduced secretion; the 150- and 250-mg doses of nizatidine suppressed secretion for at least 2.5 hr. In study 2, eight subjects received one 5-min intravenous infusion of placebo, cimetidine (300 mg), or nizatidine (25, 50, 100, or 250 mg) weekly for 6 wk. Secretion was induced by infusing pentagastrin (2 micrograms/kg/hr) 45 min before the study drug was dosed and for 3.5 hr thereafter. Again, all doses of nizatidine reduced gastric acid, chiefly by decreasing volume. Nizatidine induced a clear dose-response effect; nizatidine (100 mg) and cimetidine (300 mg) had approximately equal suppressive effects. Nizatidine (100 mg) and cimetidine (300 mg) reduced acid output by 62% and 63% and reduced volume of secretion by 48% and 51% over the 3.5-hr period. Gastric acid suppression and plasma nizatidine concentrations were directly related. Nizatidine kinetics were linear and proportional to dose. The t1/2 was 1.3 hr (range 0.7 to 2.1 hr), the volume of distribution was 1.2 +/- 0.5 l/kg, and clearance was 0.6 +/- 0.2 l/kg/hr. Laboratory abnormalities and side effects were minor in both studies.

Penicillamine kinetics in normal subjects.

The kinetic characteristics of penicillamine are reported in four fasting subjects after four oral doses each. On late test days, tow of the subjects received an additional single dose 30 min after a large breakfast. On subject originally included in the study had to drop out because of gastrointestinal disturbances following each of two single doses of penicillamine. The fasting plasma levels of penicillamine observed in this study displayed an unusual double peak in the plasma levels after single doses. Individual subjects had consistent plasma level patterns for each of the four single doses but there was marked intersubject variability in patterns and kinetic parameters. The half-life of unchanged penicillamine ranged from 1.66 to 3.15 hr and the apparent plasma clearance ranged from 530 to 2300 ml/min. The administration of penicillamine following a large breakfast caused a reduction in the area under the penicillamine plasma concentration-time curve corresponding to a decrease in the extent of absorption of unchanged penicillamine.

Relationship between steady-state plasma nizatidine concentrations and inhibition of basal and stimulated gastric acid secretion.

Steady-state plasma nizatidine concentrations were related in a linear fashion to nizatidine infusion rate. Infusion rates of 2.5, 10, and 20 mg/hr resulted in mean plasma nizatidine concentrations of 69, 247, and 575 ng/ml. Basal acid secretion was inhibited by 50% and 90% at mean plasma nizatidine concentrations of 60 and 430 ng/ml. Protein-stimulated acid secretion was inhibited by 50% and 90% at mean plasma nizatidine concentrations of 75 and 490 ng/ml. The mean pH of basal gastric secretions was 1.6 during placebo infusion and 4.6 when the mean plasma nizatidine concentration was 575 ng/ml.

Secretion of nizatidine into human breast milk after single and multiple doses.

Disposition of the H2-receptor antagonist nizatidine was studied in serum, urine, and breast milk. Five lactating women and five nonlactating women participated; the disposition of nizatidine was studied in three of the lactating women. Single and multiple doses of 150 mg nizatidine were administered orally. The disposition of nizatidine (half-life, 1 1/2 hours; apparent serum clearance, 40 L/hr; renal clearance, 27 L/hr; and apparent volume of distribution, 1.4 L/kg) was similar in lactating and nonlactating women. These pharmacokinetic results were analogous to observations for men in other studies. Nizatidine breast milk concentrations were directly proportional to corresponding serum concentrations. On average, 96 micrograms nizatidine, less than 0.1% of the maternal dose, was secreted into milk during a 12-hour interval after either single or multiple doses.

Assessment of the potential for a pharmacokinetic interaction between fluoxetine and terfenadine.

OBJECTIVE: To assess whether fluoxetine and its metabolite, norfluoxetine, are inhibitors of the metabolism of CYP3A substrates. BACKGROUND: Because inhibition of the first-pass metabolism of terfenadine may be associated with fatal arrhythmia, we assessed the possibility that fluoxetine inhibits this metabolism as a model for CYP3A drug interactions. METHODS: Male subjects (n = 12) were given two single doses of 60 mg terfenadine alone (treatment 1) and again after the eighth dose in a 9-day regimen of 60 mg fluoxetine once a day (treatment 2). Blood samples, collected up to 48 hours after each terfenadine dose, were assayed for terfenadine and terfenadine acid metabolite. The assay limits of quantification were 0.1 ng/ml and 5.0 ng/ml, respectively. Noncompartmental pharmacokinetic data for terfenadine and terfenadine acid metabolite were compared between treatments. RESULTS: Mean value +/- SD plasma concentrations of fluoxetine (165 +/- 45 ng/ml) and norfluoxetine (83 +/- 23 ng/ml) achieved after the eighth dose did not cause a significant change in terfenadine acid metabolite pharmacokinetics. All terfenadine concentrations were less than 5 ng/ml and they were approximately 30% lower after fluoxetine pretreatment compared with terfenadine alone. The area under the concentration-time curve for terfenadine was lower after fluoxetine administration, a statistically significant difference, but the peak concentration of terfenadine was not significantly different. Because most antihistaminic activity after terfenadine administration is attributed to its acid metabolite, the small decrease in terfenadine concentration is not clinically significant. No subject discontinued the drugs because of an adverse event. CONCLUSION: Fluoxetine did not inhibit the metabolism of terfenadine and is unlikely to affect the metabolism of terfenadine or other drugs that are CYP3A substrates.

Effect of fluoxetine on psychomotor performance, physiologic response, and kinetics of ethanol.

The effects of fluoxetine, a specific serotonin reuptake inhibitor, on the psychomotor performance, physiologic response, and kinetic disposition of ethanol were examined. Fluoxetine (30 or 60 mg) with ethanol (45 ml absolute alcohol per 70 kg body weight) did not alter the plasma or blood concentrations of fluoxetine or ethanol, respectively, when compared with levels after either drug alone. There was no significant effect on standing or recumbent blood pressure or heart rate after single or multiple doses of fluoxetine alone or in the combination. Single or multiple doses of fluoxetine had no effect on the psychomotor activity (stability of stance, motor performance, or manual coordination) or subjective effects of alcohol. Data indicate that fluoxetine does not inhibit ethanol metabolism nor does it have any effects on its psychomotor activity.

Fluoxetine kinetics and protein binding in normal and impaired renal function.

The effect of decreased renal function on the disposition and elimination of the nontricyclic antidepressant fluoxetine was examined in 25 adult male subjects after a single 40-mg oral dose. Blood samples for the measurement of fluoxetine and its active metabolite norfluoxetine were drawn 13 times in the first 48 hr after dosing and thrice weekly thereafter for 4 wk. All urine was collected in daily aliquots for 4 wk and was assayed for fluoxetine and norfluoxetine concentrations. The extent of fluoxetine binding to plasma protein was determined by equilibrium dialysis. Kinetic analyses were by noncompartmental methods. The drug and its metabolite were distributed over a large apparent volume and both were eliminated slowly. No correlations between the degree of renal dysfunction and the rate of elimination, volume of distribution, or protein binding were found. Plasma concentrations of fluoxetine and norfluoxetine were not significantly changed by hemodialysis.

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.

Fluoxetine: clinical pharmacology and physiologic disposition.

Fluoxetine (30 mg), administered for 7 days to normal volunteers, produced a 66% inhibition of tritiated serotonin uptake into platelets. Plasma concentrations of fluoxetine correlated positively with inhibition of serotonin uptake. Fluoxetine is well absorbed after oral administration in both the fed and fasted states and demonstrates dose proportionality. Fluoxetine disappears from plasma with a half-life of 1-3 days; its metabolite norfluoxetine has a plasma half-life of 7-15 days. After administration of 14C-fluoxetine, approximately 65% of the administered dose of radioactivity is recovered in urine and about 15% in feces. Fluoxetine, given as a single dose or in multiple doses over 8 days, did not produce significant effects on the plasma disappearance of warfarin, diazepam, tolbutamide, or chlorothiazide. Coadministration of fluoxetine and ethanol did not result in an increase from control values in the blood ethanol levels, nor did it produce significant changes in physiologic, psychometric, or psychomotor activity. Pharmacokinetics of fluoxetine in the elderly and normal volunteers appear to be similar. In addition, pharmacokinetic analyses in patients with varying degrees of renal impairment did not show significant differences from healthy subjects.

Nizatidine, and H2-receptor antagonist: disposition and safety in the elderly.

Nizatidine is an orally active H2-receptor blocker. Its disposition and safety in eight young and 12 elderly volunteers were investigated. Single oral doses of nizatidine were administered: from 100 mg to 300 mg in the elderly, and from 100 mg to 350 mg in the young. The nizatidine AUC was directly proportional to dose for both groups. Calculated pharmacokinetic variables in the elderly vs. the young were t1/2 = 1.9 vs. 1.6 hr; CLp/f = 32 vs. 40 L/hr, and Vd beta/f = 1.2 vs. 1.3 L/kg. The impaired renal function of some elderly volunteers prolonged nizatidine elimination and lowered its clearance. Renal impairment rather than advanced age per se was the predominant factor in decreasing the nizatidine elimination rate. Because Clcr correlated directly with nizatidine renal clearance, Clcr values may be used to estimate nizatidine dosage reductions in renal insufficiency. During the trial, no serious adverse effects occurred.

Single-dose and steady-state pharmacokinetics of tomoxetine in normal subjects.

A pharmacokinetic profile of tomoxetine, a selective norepinephrine uptake inhibitor, was developed in human volunteers following single and multiple oral administrations. Following the administration of a single 90-mg oral dose of tomoxetine to four normal volunteers, the plasma half-life was 4.3 +/- 0.5 hours. Mean plasma clearance was 0.60 +/- 0.14 L/Kg/hr, and the mean volume of distribution was 3.7 +/- 0.9 L/kg. Multiple doses of tomoxetine (20 mg bid and 40 mg bid) for seven days were administered to an additional seven subjects. The data appeared to have a bimodal distribution. The mean plasma half-life determined following the last dose was 4.6 +/- 0.5 hours in five subjects. The other two subjects, one at each dose level, demonstrated accumulation of tomoxetine occurring from the first to last dose where tomoxetine disappeared from plasma with a mean half-life of 19 hours.

Clinical pharmacokinetics of intravenously injected tritiated vinzolidine.

Vinzolidine (VZL), a novel, semi-synthetic vinca alkaloid showing evidence of oncolytic activity in phase I/II clinical trials, was studied in six patients for its pharmacokinetic and metabolic behavior. Following i.v. administration of [3H]-VZL at doses of 5, 6.7, and 9 mg/m2, blood and urine samples were collected and analyzed by sample oxidation and HPLC. Following a single i.v. dose, decay of total tritium in plasma was tetraphasic, with a rapid initial t1/2 alpha of 0.044 +/- 0.013 h, followed by a t1/2 beta of 0.54 +/- 0.22 h and a t1/2 gamma of 9.48 +/- 4.89 h; the terminal t1/2 gamma was 219 +/- 57 h. The mean plasma clearance of total tritium was 0.054 +/- 0.044 l.kg/h, and the mean volume of distribution was 14.3 +/- 5.4 l/kg; mean urinary excretion was 13.6% +/- 4.3% of the delivered radioactivity. Qualitative analysis of plasma and urine revealed the predominance of unchanged VZL plus two unidentified metabolites with different elution times. In comparison with oral VZL, as previously reported, i.v. injected VZL showed comparable values with respect to the volume of the central compartment (VC), plasma clearance (Clp), and terminal t1/2 for total tritium. Qualitatively, the metabolites observed in plasma and urine were comparable in number and quantity with values obtained in analyses after oral administration.

Lack of effect of olanzapine on the pharmacokinetics of a single aminophylline dose in healthy men.

STUDY OBJECTIVE: To test whether olanzapine, an atypical antipsychotic, is an inhibitor of cytochrome P450 (CYP) 1A2 activity, we conducted a drug interaction study with theophylline, a known CYP1A2 substrate. DESIGN: Two-way, randomized, crossover study. SETTING: Clinical research laboratory. SUBJECTS: Nineteen healthy males (16 smokers, 3 nonsmokers). INTERVENTIONS: Because the a priori expectation was no effect of olanzapine on theophylline pharmacokinetics, a parallel study using cimetidine was included as a positive control. In group 1, 12 healthy subjects received a 30-minute intravenous infusion of aminophylline 350 mg after 9 consecutive days of either olanzapine or placebo. In group 2, seven healthy subjects received a similar aminophylline infusion after 9 consecutive days of either cimetidine or placebo. MEASUREMENTS AND MAIN RESULTS: Concentrations of theophylline and its metabolites in serum and urine were measured for 24 and 72 hours, respectively. Plasma concentrations of olanzapine and its metabolites were measured for 24 hours after the next to last dose and 168 hours after the last olanzapine dose. Olanzapine did not affect theophylline pharmacokinetics. However, cimetidine significantly decreased theophylline clearance and the corresponding formation of its metabolites. Urinary excretion of theophylline and its metabolites was unaffected by olanzapine but was reduced significantly by cimetidine. Steady-state concentrations of olanzapine (15.3 ng/ml), 10-N-glucuronide (4.9 ng/ml), and 4'-N-desmethyl olanzapine (2.5 ng/ml) were observed after olanzapine 10 mg once/day and were unaffected by coadministration of theophylline. CONCLUSION: As predicted by in vitro studies, steady-state concentrations of olanzapine and its metabolites did not affect theophylline pharmacokinetics and should not affect the pharmacokinetics of other agents metabolized by the CYP1A2 isozyme.

The effects of renal and hepatic disease on the pharmacokinetics, renal tolerance, and risk-benefit profile of fluoxetine.

Renal and hepatic diseases have a significant impact on the plasma concentration profiles and the dose requirements for almost all drugs. This paper reviews the effect of these diseases and their associated physiological derangements on the pharmacokinetics of fluoxetine and norfluoxetine. Metabolic studies of fluoxetine in man show that more than 70% of the radiolabelled compound is excreted in the urine. Most of the urinary radiolabelled products are metabolites and not the parent compound nor its active metabolite, norfluoxetine. Cirrhosis of the liver significantly reduces the clearance of fluoxetine and norfluoxetine, but mild, moderate, or severe renal dysfunction does not affect fluoxetine or norfluoxetine pharmacokinetics. Daily administration of fluoxetine, 20 mg, for more than 2 months to renally impaired, depressed patients (who require haemodialysis) produces steady-state fluoxetine and norfluoxetine plasma concentrations that are comparable to the concentrations in depressed patients with normal renal function. Renal function is not an important determinant of the steady-state concentrations of fluoxetine or norfluoxetine, though the concentrations may be higher in patients with significantly impaired liver function.