Disposition and biotransformation of the antipsychotic agent olanzapine in humans.

Disposition and biotransformation of the new antipsychotic agent olanzapine (OLZ) were studied in six male healthy volunteers after a single oral dose of 12.5 mg containing 100 microCi of [14C]OLZ. Biological fluids were analyzed for total radioactivity, the parent compound (GC/MS), and metabolites (electrospray LC/MS and LC/MS/MS). Mean radiocarbon recovery was approximately 87%, with 30% appearing in the faces and 57% excreted in the urine. Approximately half of the radiocarbon was excreted within 3 days, whereas > 70% of the dose was recovered within 7 days of dosing. Circulating radio-activity was mostly restricted to the plasma compartment of blood. Mean peak plasma concentration of OLZ was 11 ng/ml, whereas that of radioactivity was 39 ng eq/ml. Mean plasma terminal elimination half-lives were 27 and 59 hr, respectively, for OLZ and total radioactivity. With the help of NMR and MS data, a major metabolite of OLZ in humans was characterized as a novel tertiary N-glucuronide in which the glucuronic acid moiety is attached to the nitrogen at position 10 of the benzodiazepine ring. Another N-glucuronide was detected in urine and identified as the quaternary N-linked 4'-N-glucuronide. Oxidative metabolism on the allylic methyl group resulted in 2-hydroxymethyl and 2-carboxylic acid derivatives of OLZ. The methyl piperazine moiety was also subject to oxidative attack, giving rise to the N-oxide and N-deemethyl metabolites. Other metabolites, including the N-deemethyl-2-carboxy derivative, resulted from metabolic reactions at both the 4' nitrogen and 2-methyl groups. The 10-N-glucuronide and OLZ were the two most abundant urinary components, accounting for approximately 13% and 7% of the dose, respectively. In fecal extracts, the only significant radioactive HPLC peaks were due to 10-N-glucuronide and OLZ representing, respectively, approximately 8% and 2% of the administered dose. Semiquantitative data obtained from plasma samples from subjects given [14C]OLZ suggest that the main circulating metabolite is 10-N-glucuronide. Thus, OLZ was extensively metabolized in humans via N-glucuronidation, allylic hydroxylation, N-oxidation, N-dealkylation and a combination thereof. The 10-N-glucuronidation pathway was the most important pathway both in terms of contribution to drug-related circulating species and as an excretory product in feces and urine.

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.

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.

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.

Pressor responses to tyramine and norepinephrine after subchronic administration of fluoxetine to man.

The effects of subchronic, oral administration of fluoxetine (60 mg daily for 45 days) were studied in three healthy male volunteers. The pressor responses to intravenous bolus tyramine injections or norepinephrine infusions were assessed during the one-week placebo period, periodically after daily fluoxetine dosing, and then for 11 days post-fluoxetine dosing. The dose-pressor responses, determined from the incremental elevation of systolic blood pressure, were unchanged in each of the three dosing intervals. These results indicate that fluoxetine does not significantly impair the catecholamine uptake mechanism in the peripheral adrenergic neuron on acute or subchronic dosing, nor is any rebound-increased sensitivity evident after subchronic administration. Further, fluoxetine does not appear to demonstrate peripheral alpha-adrenolytic properties in man.

Early clinical evaluation in man: the buck stops here.

The development of new drugs as potential therapeutic agents involves multi-discipline 'team' research. The clinician has to deal with scientific and ethical issues and keep in mind the axiom 'Primum no nocere--Above all, do no harm.' The clinical pharmacologist has to address the pharmacologic actions of a potential new drug and if any antidotes are available. Species in pharmacologic actions, assessment of animal laboratory data to determine the sensitive organs, and the role of drug metabolism in evaluating and correlating animal data all need to be addressed. The clinical pharmacologist has an important role in new drug development which is unique and includes the responsibility to ensure the welfare of the volunteer subjects or patients.

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.

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.

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.

Clinical pharmacology of tomoxetine, a potential antidepressant.

Tomoxetine (LY139603) selectively inhibits norepinephrine uptake in animals and has activity in animal models of depression. Tomoxetine was administered in single oral doses up to 90 mg to healthy normal volunteers. In addition, normal human subjects received either 20 or 40 mg of tomoxetine b.i.d. for 1 week to evaluate the safety and pharmacologic activity of the compound in humans. At these doses, no serious drug-related adverse effects were encountered. Activity of the compound at the lower dose (20 mg b.i.d.) was evaluated by examining changes in the pressor responses to infused norepinephrine and tyramine and by determining [3H]serotonin uptake in platelets harvested from subjects receiving the compound. Pressor sensitivity to norepinephrine was increased by 261 +/- 69% of control, and pressor sensitivity to tyramine was decreased by 51 +/- 6% of control during treatment. Changes in the pressor sensitivity to norepinephrine in individual subjects were positively correlated with drug levels. There were no statistically significant changes in platelet [3H]serotonin uptake. These results indicate that tomoxetine selectively inhibits norepinephrine uptake in humans at doses which are clinically well tolerated and suggest that tomoxetine has potential clinical use as an antidepressant.

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.

Pharmacological activity of the basic fraction of marihuana whole smoke condensate alone and in combination with delta-9-tetrahydrocannabinol in mice.

This basic fraction (BF) of marihuana whole smoke condensate was subjected to pharmacological testing in males, Swiss-Webster mice. In a general pharmacological activity screen looking at behavioral, neurologic, and autonomic parameters, BF, at iv doses of 5, 10, and 20 mg/kg, caused impairment of visual placing, increase in tail pinch response, decrease in tail elevation, and induction of piloerection. These effects, although statistically significant, were slight and not consistently dose dependent. In a second study with doses ranging from 10 to 29 mg/kg, BF caused a decrease in spatial locomotion, rearing behavior, and urination incidence. In a third study, body temperatures of mice were measured periodically for 2 hr following administration of BF (1.2, 2.4, and 4.8 mg/kg) alone or in combination with 1.0 mg/kg delta-9-tetrahydrocannabinol (THC). BF did not alter body temperature, nor did it affect THC-induced hypothermia. These results, although suggesting that the basic fraction of marihuana whole smoke condensate has pharmacological activity in mice, offers little evidence for the presence of highly active compounds.