Pharmacodynamics and pharmacokinetics of levofloxacin

Principles of antibiotic pharmacodynamics include factors that are important for effective eradication of bacteria as well as the suppression of resistance. For effective eradication of bacteria and a good clinical outcome, a ratio for the area under the plasma concentration-time curve relative to the minimum inhibitory concentration (AUC/MIC) of greater than 100 is needed for gram-negative organisms, and a level of greater than 30 is required for gram-positive organisms. Pharmacodynamic principles can also be used to devise the optimal administration regimen for specific antimicrobial agents. Pharmacodynamic analysis of the activity of levofloxacin against Streptococcus pneumoniae revealed that, 99% of the time, actual hospitalized patients achieve an AUC/MIC of greater than 30. This indicates that levofloxacin will be very effective in treating S. pneumoniae infections in the majority of patients. Cost of treatment is an increasing concern voiced by healthcare providers and users alike. This has led to a much greater emphasis placed upon the cost of individual drugs used in the management of infections. However, when evaluating the cost of an antibiotic, it is extremely important that not only are the direct acquisition costs assessed, but consideration also given to other aspects incurring a financial burden, such as drug preparation cost, supplies, costs of treating adverse events or any treatment failures. It is only by having such a full assessment of costs that realistic financial comparisons can be made between different antibiotics.     

Pharmacodynamics and pharmacokinetics of the oral antispastic agent tizanidine in patients with spinal cord injury

The efficiency and duration of action of a single oral dose (8 mg) of tizanidine in patients with spinal cord injuries were determined by studying its antispastic, cardiovascular and sedative effects along with its pharmacokinetic profile in five tetraplegic and five paraplegic patients. After the administration of tizanidine, there was a reduction in spasticity in both groups within half an hour, with the effects lasting for 3 to 4 hours. There was no rebound increase in blood pressure. There was a greater increase in sedation in the tetraplegics than in the paraplegics. Plasma tizanidine levels rose within half an hour after dosing and peaked at one hour. The levels had fallen to 15 percent by 6 hours. The plasma half-life was 2.7 +/- 0.06 hours. We conclude that oral tizanidine has antispastic effects in patients with spinal cord injuries without affecting the power of non-involved muscle groups. It has minimal effects on blood pressure and it lowers heart rate. Side effects include sedation and dryness of mouth.     

Pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine.

The pharmacodynamics and pharmacokinetics of intramuscular dexmedetomidine--a novel alpha 2-adrenergic receptor agonist under development for preanesthetic use--were studied in healthy male volunteers. Single intramuscular doses of dexmedetomidine (0.5, 1.0, and 1.5 microgram/kg) and placebo were administered to six subjects in a single-blind, multiple crossover study. Dexmedetomidine induced dose-related impairment of vigilance assessed both objectively and subjectively. The drug also caused moderate decreases in blood pressure and heart rate. Plasma norepinephrine was dose-dependently (maximum 89%) decreased. The intramuscular doses resulted in linearly dose-related plasma concentrations of dexmedetomidine. Pharmacokinetic calculations revealed a time to maximum concentration from 1.6 to 1.7 hours, an elimination half-life of 1.6 to 2.4 hours, an apparent total plasma clearance of 0.7 to 0.9 L/hr/kg, and apparent volume of distribution of 2.1 to 2.6 L/kg. The sedative effect of dexmedetomidine dissipated during the 6-hour observation time, but all other effects were still evident 6 hours after administration of the higher doses, paralleling the plasma concentration curves. The relationship of plasma concentrations of dexmedetomidine to pharmacodynamic variables was consistent with a linear pharmacodynamic model. The pharmacodynamic-pharmacokinetic profile of intramuscular dexmedetomidine may be suited to the proposed preanesthetic clinical use of this alpha 2-agonist.     

Pharmacodynamics of intravenous labetalol and follow-up therapy with oral labetalol

The effectiveness, safety, and pharmacodynamics of repeated doses of intravenous labetalol for rapid reduction of severe hypertension and of subsequent oral labetalol dosing were studied. Twelve patients with severe hypertension were admitted to the hospital after the withholding of antihypertensive therapy for 2 to 14 days. Thirty minutes after an injection of vehicle only, labetalol, 0.25 mg/kg body weight, was injected and followed by repeat injections of 0.5 mg/kg every 15 minutes until the supine diastolic blood pressure (BP) was reduced to less than 90 mm Hg or a total of 3.25 mg/kg had been administered. Twenty-four hours after the last injection, oral labetalol was started at an initial dosage of 100 or 200 mg b.i.d., then increased every 2 days until the standing diastolic BP was less than 90 mm Hg or a maximum daily dosage of 2400 mg was reached. The initial injection achieved mean falls in supine systolic/diastolic BPs of 11/7 mm Hg. Subsequent injections produced additional falls in a dose-related fashion; the mean falls after the last injection (total cumulative dose 2.7 mg/kg) were 40/20 mm Hg. The effect lasted for 12 hours or more in most patients and tended to be biphasic, with one peak at approximately 5 minutes and another much less pronounced peak at about 4 hours. There was no evidence of precipitous falls in BP. All patients were able to ambulate 6 hours after the last injection without symptoms of postural hypotension. Oral labetalol effectively and safely restored and maintained the BP reductions achieved with intravenous labetalol.     

Plasma and oral fluid pharmacokinetics and pharmacodynamics after oral codeine administration

BACKGROUND: The ease, noninvasiveness, and safety of oral fluid collection have increased the use of this alternative matrix for drugs-of-abuse testing; however, few controlled drug administration data are available to aid in the interpretation of oral fluid results. METHODS: Single oral codeine doses (60 and 120 mg/70 kg) were administered to 19 volunteers. Oral fluid and plasma were analyzed for free codeine, norcodeine, morphine, and normorphine by solid-phase extraction combined with gas chromatography-mass spectrometry (SPE/GC-MS). Physiologic and subjective effects were examined. RESULTS: Mean (SE) peak codeine concentrations were 214.2 +/- 27.6 and 474.3 +/- 77.0 micro g/L in plasma and 638.4 +/- 64.4 and 1599.3 +/- 241.0 micro g/L in oral fluid. The oral fluid-to-plasma ratio for codeine was relatively constant ( approximately 4) from 1 to 12 h. The mean half-life (t(1/2)) of codeine was 2.2 +/- 0.10 h in plasma and 2.2 +/- 0.16 h in oral fluid. Significant dose-related miosis and increases in sedation, psychotomimetic effect, and "high" occurred after the high dose. Mean codeine oral fluid detection time was 21 h with a 2.5 microg/L cutoff, longer than that of plasma (12-16 h). Detection times with the proposed Substance Abuse and Mental Health Services Administration cutoff (40 microg/L) were only 7 h. Norcodeine, but not morphine or normorphine, was quantified in both plasma and oral fluid. CONCLUSIONS: The disposition of codeine over time was similar in plasma and oral fluid, but because of high variability, oral fluid codeine concentrations did not reliably predict concurrent plasma concentrations. Oral fluid testing is a useful alternative matrix for monitoring codeine exposure with a detection window of 7-21 h for single doses, depending on cutoff concentrations. These controlled drug administration data should aid in the interpretation of oral fluid codeine results.     

Human pharmacokinetics and tolerance of oral ganciclovir.

Ganciclovir is a nucleoside analog which inhibits the replication of herpesviruses in vitro and which has been effective by intravenous administration for the treatment of severe cytomegalovirus infection in immunocompromised patients. Because most patients with acquired immunodeficiency syndrome and severe cytomegalovirus infection have required lifelong daily suppressive ganciclovir therapy to control disease progression, oral therapy appears to have practical advantages. We studied the pharmacokinetics of orally administered ganciclovir in four patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. Repeated oral ganciclovir doses (10 to 20 mg/kg every 6 h) were well tolerated. With a 20-mg/kg dose given every 6 h, mean steady-state peak and trough levels were 2.96 and 1.05 microM, respectively, and the area under the concentration-time curve from 0 to 24 h was 47 microM X h. Calculated absorption was 3.0%, based on urinary excretion. Because the levels achieved in serum with oral ganciclovir approximated those required to inhibit cytomegalovirus in vitro, a trial of oral maintenance therapy in immunocompromised patients with severe cytomegalovirus infections seems warranted.     

Pharmacodynamics and pharmacokinetics of the urotensin II receptor antagonist palosuran in macroalbuminuric, diabetic patients

OBJECTIVE: In patients with renal disease increased urotensin II plasma levels have been observed. We have investigated whether palosuran, a potent, selective, and competitive antagonist of the urotensin II receptor, has effects in patients who are prone to the development of renal disease. METHODS: Macroalbuminuric, diabetic patients, categorized by renal function, were treated with oral doses of 125 mg palosuran twice daily for 13.5 days in addition to treatment with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. The 24-hour urinary albumin excretion rate was determined twice at baseline and after 13.5 days of treatment. Plasma concentrations of palosuran were determined for 12 hours after the first and last drug intake. Renal hemodynamics was measured before and after 12.5 days of treatment. Tolerability and safety parameters were monitored. RESULTS: An overall clinically significant reduction of 24.3% (geometric mean) (95% confidence interval, 4.1 to 45.0) in the 24-hour urinary albumin excretion rate was observed (P = .014). No effect was observed on renal hemodynamic parameters. Palosuran was rapidly absorbed with maximum plasma concentrations at 1 hour after drug administration. The accumulation factor was 1.7 (geometric mean) (95% confidence interval, 1.3 to 2.1). Palosuran was well tolerated. CONCLUSIONS: The good tolerability profile and the decrease in the 24-hour urinary albumin excretion rate may benefit diabetic patients with renal failure with regard to their disease progression. Larger placebo-controlled trials in this patient population are needed to investigate whether urotensin II receptor antagonists, given as monotherapy or combination therapy, may improve the current treatment of diabetic nephropathy.     

Population pharmacokinetics of long-term oral amiodarone therapy

BACKGROUND: Amiodarone is an increasingly popular and uniquely effective antiarrhythmic agent for which population pharmacokinetic parameters in patients receiving long-term oral therapy have not been defined previously. METHODS: We collected 605 observations of serum amiodarone and desethylamiodarone metabolite concentrations from 77 patients (mean follow-up, 2 years). Mixed-effects modeling (NONMEM) was used to determine the typical population pharmacokinetic parameters, their respective variabilities, and a simple oral dosing regimen to rapidly achieve and maintain a target concentration of 1.5 mg/L. Individual serum concentration versus time curves were simulated for the study population based on regimens outlined in the product monograph and were compared with those for the proposed dosing regimen. The relationship between the duration of amiodarone therapy and the rate of decrement in serum concentration after discontinuation was explored. RESULTS: Amiodarone concentrations were best described by a two-compartment model with the typical parameters +/- interindividual coefficients of variation (where applicable) as follows: volumes of distribution/bioavailability (V1/F = 882 L; V2/F = 12,700 L +/- 58%) and clearances/bioavailability (CL1/F = 229 L/day +/- 31%; and CL2/F = 599 L/day +/- 56%). Rapid distribution half-life was 17 hours, and terminal half-life was 55 days. A practical dosing regimen of 1600 mg/d for 2 days, 1,200 mg/d for 5 days, 1,000 mg/d for 7 days, 800 mg/d for 7 days, 600 mg/d for 7 days, and 400 mg/d for 62 days followed by a maintenance dose of 343 mg/d (400 mg/d for 6 of 7 days) is proposed. After steady state is reached, cessation of dosing produces a 25% serum concentration decrement in 3 days and 50% in 36 days. CONCLUSIONS: Population pharmacokinetics confirm that amiodarone has an extraordinarily long half-life. The slow elimination rate makes anticipating the timing of adjustments in amiodarone therapy to avoid toxicity unusually perplexing. However, based on the estimated variability, the proposed dosing regimen would produce steady-state concentrations within the therapeutic window for 90% of patients.     

Effect of pirmenol on premature atrial complexes

Suppression of premature atrial complexes by pirmenol, a new Class I antiarrhythmic agent, was examined following oral and intravenous routes of administration. In 4 patients, single intravenous doses of 50 to 150 mg reduced premature atrial beats greater than or equal to 90% for 2 to 4 h. Oral doses of 75 to 200 mg twice daily induced a mean arrhythmia reduction of greater than or equal to 80% in 5 out of 9 patients during a 24-h electrocardiographic recording compared with a baseline period of 48 h. No significant side-effects occurred. The results indicate that pirmenol effectively suppresses premature atrial complexes, which may be of value in the prevention of supraventricular tachyarrhythmias.     

Pharmacodynamics of immunosuppression by mycophenolic acid: inhibition of both lymphocyte proliferation and activation correlates with pharmacokinetics

Mechanisms of immunosuppressive action of mycophenolic acid (MPA) on rat lymphocytes and correlations among MPA plasma concentrations (pharmacokinetics) and its suppression of immune functions (pharmacodynamics) were studied in vitro and in vivo. In vitro, MPA inhibited concanavalin A-stimulated lymphocyte proliferation in blood [tritium-labeled thymidine ([(3)H]TdR) incorporation, percentage of lymphocytes positive for proliferating cell nuclear antigen, and in S-G(2)M by flow cytometry] and activation (percentage of lymphocytes expressing CD25 or CD134). Maximum percent inhibitions (I(max)) of lymphocyte functions and concentrations of MPA (mg/l in blood) inhibiting 50% of I(max) (IC(50)) were 99%/0.14 mg/l for [(3)H]TdR, 93%/0.28 mg/l for S-G(2)M, 74%/0.29 mg/l for CD25, and 83%/0.24 mg/l for CD134. Blood sampled at different times after single or multiple oral MPA administrations at four dose levels was assayed for lymphocyte functions and MPA plasma concentrations. I(max) (%) and IC(50) (mg/l in plasma by HPLC) were 98 to 99%/0.18 to 0.19 mg/l for [(3)H]TdR, 88 to 98%/0.70 to 0.83 mg/l for S-G(2)M, 60 to 63%/0.65 to 0.81 mg/l for CD25, and 72 to 77%/0.61 to 0.74 mg/l for CD134. IC(50) values for S-G(2)M, CD25, and CD134 were higher after multiple daily treatments than after a single dose. There were clear and direct relationships among MPA dose levels, kinetics of MPA plasma concentrations, and dynamics of lymphocyte functions. MPA treatment in vitro and in vivo inhibits not only mitogen-stimulated lymphocyte proliferation in whole blood but also lymphocyte expression of cell surface cytokine receptors. These two different mechanisms of action may contribute to the therapeutic efficacy of MPA in vivo.     

Multiple-dose safety and pharmacokinetics of oral garenoxacin in healthy subjects

Garenoxacin (T-3811ME, BMS-284756) is a novel des-F(6) quinolone that has been shown to be effective in vitro against a wide range of clinically important pathogens, including gram-positive and gram-negative aerobes and anaerobes. This study was conducted to evaluate the safety and tolerability of multiple oral doses (100 to 1200 mg/day) of garenoxacin in healthy subjects and to determine its multiple-dose pharmacokinetics. Forty healthy male and female subjects (18 to 45 years of age) were enrolled in this randomized, double-blind, placebo-controlled, sequential, multiple- and ascending-dose study. Each subject received a once-daily oral dose of garenoxacin (100, 200, 400, 800, or 1200 mg) or a placebo for 14 days. Blood and urine samples were collected for measurements of garenoxacin by validated liquid chromatography with dual mass spectrometry, and plasma garenoxacin concentration-time data were analyzed by noncompartmental methods. The effects of garenoxacin on Helicobacter pylori, psychometric test performance, and electrocardiograms were assessed, as was drug safety. Over the 14 days of dosing, geometric mean peak concentrations of garenoxacin in plasma (C(max)) at the 100- and 1200-mg doses were within the ranges of 1.2 to 1.6 and 16.3 to 24 microg/ml, respectively. The corresponding values for the geometric mean area under the concentration-time curve over the dosing interval (AUC(tau)) for garenoxacin in plasma at the 100- and 1200-mg doses were within the ranges of 11.5 to 15.7 and 180 to 307 microg. h/ml, respectively. Increases in systemic exposure to garenoxacin in terms of AUC and C(max) were approximately dose proportional over the 100- to 400-mg dose range but demonstrated increases that were somewhat greater than the dose increments at the 800- and 1200-mg doses. Median values for the time to achieve C(max) were in the range of 1.13 to 2.50 h for all doses. The mean elimination half-life for garenoxacin in plasma appeared to be independent of dose and ranged from 13.3 to 17.8 h (day 14). Approximately 30 to 50% of an administered garenoxacin dose was excreted unchanged in the urine. At doses of 100 to 400 mg, steady-state concentrations of garenoxacin in plasma appeared to be attained by the fourth dose. Multiple oral doses of garenoxacin were well tolerated and did not demonstrate clinically significant effects on QT(c) or psychometric test results. Garenoxacin administered alone for 14 days at doses of >or=400 mg demonstrated activity against H. pylori. These results suggest that multiple once-daily oral doses of garenoxacin of up to 1200 mg are safe and well tolerated and that the pharmacokinetics of garenoxacin support once-daily administration.     

Human intravenous pharmacokinetics and absolute oral bioavailability of cefatrizine.

Cefatrizine was administered intravenously and orally at dose levels of 250, 500, and 1,000 mg to normal male volunteers in a crossover study. Intravenous pharmacokinetics were dose linear over this range; mean peak plasma concentrations at the end of 30-min infusions were, respectively, 18, 37, and 75 micrograms/ml, total body clearance was 218 ml/min per 1.73 m2, renal clearance was 176 ml/min per 1.73 m2, and mean retention time in the body was 1.11 h. Cumulative urinary excretion of intact cefatrizine was 80% of the dose, and half-lives ranged from 1 to 1.4 h. Steady-state volume of distribution was 0.22 liters/kg. On oral administration, the absolute bioavailabilities of cefatrizine were 75% at 250 and 500 mg and 50% at 1,000 mg. The mean peak plasma concentrations and peak times were, respectively, 4.9, 8.6, and 10.2 micrograms/ml at 1.4, 1.6, and 2.0 h, mean residence times were 2.4, 2.6, and 3.1 h, and mean absorption times were 1.3, 1.6, and 1.9 h. Oral renal clearance and half-life values corresponded well to the intravenous values. Cumulative urinary excretion of intact cefatrizine (as percentage of dose) was 60 at 250 mg, 56 at 500 mg, and 42 at 1,000 mg. It is hypothesized that the lack of oral dose linearity between the 500- and 1,000-mg doses is due to a component of cefatrizine absorption by a saturable transport process. Relative absorption at the high dose would be sufficiently slow that an absorption "window" would be passed before maximum bioavailability could be attained. It is not expected that the observed bioavailability decrease at doses exceeding 500 mg will have any therapeutic significance, since clinical studies are establishing efficacy for a recommended unit dosage regimen of 500 mg.     

Difloxacin metabolism and pharmacokinetics in humans after single oral doses

By using high-performance liquid chromatography, the metabolism and pharmacokinetics of difloxacin were characterized in humans after single oral doses of 200, 400, and 600 mg. Group mean peak levels in plasma were obtained 4 h after administration. The means of the individual peak levels for the 200-, 400-, and 600-mg groups were 2.17, 4.09, and 6.12 micrograms/ml, respectively. The mean respective terminal-phase half-lives were 20.6, 27.1, and 28.8 h; the mean half-life for all subjects was 25.7 h. Within the dose range studied, the behavior of difloxacin could be well described by a set of linear pharmacokinetic parameters with a one-compartment open model. Levels of unconjugated metabolites in plasma were negligible. The major urinary components were difloxacin and its glucuronide, each accounting for roughly 10% of the dose. Also present were the N-desmethyl and N-oxide metabolites, accounting for 2 to 4%. Trace levels of other metabolites were observed. Group mean renal clearances ranged from 4.1 to 5.6 ml/min, indicating extensive reabsorption from the glomerular filtrate. As a result, the terminal phase half-life and the dose-normalized area under the curve were substantially greater than those of other members of the class.     

Steady-state pharmacokinetics of intravenous and oral ciprofloxacin in elderly patients.

The steady-state pharmacokinetics of ciprofloxacin were evaluated in nine elderly patients with lower respiratory tract infections after an intravenous dosage regimen of 200 mg every 12 h (n = 9) and an oral dosage regimen of 750 mg every 12 h (n = 6). Ciprofloxacin concentrations in serum and urine were measured by high-performance liquid chromatography. The peak concentration in serum, total body clearance (CLs), steady-state volume of distribution (Vss), and terminal elimination half-life after intravenous dosing were 3.5 +/- 0.8 micrograms/ml, 4.38 +/- 1.80 ml/min per kg, 1.6 +/- 0.6 liters/kg, and 5.8 +/- 2.4 h, respectively. The peak concentration in serum, time to peak concentration in serum, absorption lag time, and absolute bioavailability (F) after oral dosing were 7.6 +/- 2.2 micrograms/ml, 1.9 +/- 1.0 h, 0.4 +/- 0.5 h, and 7.7 +/- 24.2%, respectively. The elevated drug concentrations in serum samples from the elderly after oral dosing, compared with data obtained from younger subjects, appear to be a function of reduced CLs, renal clearance, and Vss. The increased F observed in some patients may be due to the effect of concomitant or proximate administration of tube feedings, medications which may alter gastric motility or acidity, or decreased first-pass metabolism. The results demonstrate that factors related to age and declining renal function, rather than infectious disease state, may be primary in determining alterations in pharmacokinetic parameters in the elderly. In elderly patients with normal renal function for their age, no dosage adjustment for intravenous or oral ciprofloxacin is necessary.     

Ethnic differences and relationships in the oral pharmacokinetics of nifedipine and erythromycin

OBJECTIVE: Our objective was to investigate ethnic differences in the oral pharmacokinetics of nifedipine and erythromycin, both typical cytochrome P4503A (CYP3A) substrates, in Koreans and Caucasians and to identify the nature of any correlations between the pharmacokinetic parameters of the two drugs. METHODS: Twenty healthy male volunteers (10 Koreans and 10 Caucasians) received single oral doses of nifedipine (10 mg) or erythromycin (500 mg) in a randomized 2-way crossover study. Pharmacokinetic evaluations were performed, and parameters were compared for the two ethnic groups. During the nifedipine study period, hemodynamic measurements were conducted to determine the pharmacodynamic relevance of the pharmacokinetic differences. RESULTS: Koreans showed area under the concentration-time curves (AUCs) for both drugs that were 1.6 to 1.7 times higher than those of Caucasians. This difference decreased to 1.3 when normalized for body weight. Significant correlation between the AUCs of the two drugs was not evident. Hemodynamic changes after nifedipine administration paralleled those of the pharmacokinetic differences, with significantly greater decreases in blood pressure and total peripheral resistance noted in Koreans. CONCLUSIONS: Koreans showed significantly lower oral clearances of nifedipine and erythromycin, probably because of genetic differences attributed to the CYP3A enzymes.     

Plasma and human leukemic cell pharmacokinetics of oral and intravenous 4-demethoxydaunomycin

On 3 consecutive days, 4-demethoxydaunomycin (D-DNM) was administered orally (30 mg/m2) as bolus injection and 4- or 24-hour infusion to seven patients with acute leukemia. Cellular (nucleated blood and bone marrow cells) and plasma drug concentrations were studied. After bolus injection, peak plasma D-DNM concentrations were about 50 mg/ml. D-DNM plasma t1/2s were 0.4 +/- 0.3 hours (T1/2 alpha) and 16.4 +/- 4.7 hours (T1/2 beta). D-DNM concentrations in nucleated blood and bone marrow cells were on the same order of magnitude and amounted to more than 400 times the plasma concentration, whereas 4-demethoxydaunomycinol (D-DNMol) concentrations were about 200 times higher. Cellular D-DNM concentrations were maximal at the end of intravenous dosing and at 2 to 4 hours after D-DNM ingestion. D-DNMol concentrations increased more slowly and accumulated on subsequent treatment days in cells and plasma; D-DNM and D-DNMol cellular t1/2 times were 42 and 72 hours, respectively. Antileukemic activity was observed.     

The effect of rifampin on the pharmacokinetics of oral and intravenous ondansetron

BACKGROUND: Ondansetron is an antiemetic agent metabolized by cytochrome P450 (CYP) enzymes. Rifampin (INN, rifampicin) is a potent inducer of CYP3A4 and some other CYP enzymes. We examined the possible effect of rifampin on the pharmacokinetics of orally and intravenously administered ondansetron. METHODS: In a randomized crossover study with 4 phases and a washout of 4 weeks, 10 healthy volunteers took either 600 mg rifampin (in 2 phases) or placebo (in 2 phases) once a day for 5 days. On day 6, 8 mg ondansetron was administered either orally (after rifampin and placebo) or intravenously (after rifampin and placebo). Ondansetron concentrations in plasma were measured up to 12 hours. RESULTS: The mean total area under the plasma concentration-time curve [AUC(0-infinity)] of orally administered ondansetron after rifampin pretreatment was reduced by 65% compared with placebo (P < .001). Rifampin decreased the peak plasma concentration of oral ondansetron by about 50% (from 27.2+/-3.0 to 13.8+/-1.5 ng/mL [mean +/- SEM]; P < .001]) and the elimination half-life (t1/2) by 38% (P < .01). The bioavailability of oral ondansetron was reduced from 60% to 40% (P < .01) by rifampin. The clearance of intravenous ondansetron was increased 83% (from 440+/-38.4 to 805+/-44.6 mL/min [P < .001]) by rifampin. Rifampin reduced the t1/2 of intravenously administered ondansetron by 46% (P < .001) and the AUC(0-infinity) by 48% (P < .001). CONCLUSIONS: Rifampin considerably decreases the plasma concentrations of ondansetron after both oral and intravenous administration. The interaction is most likely the result of induction of the CYP3A4-mediated metabolism of ondansetron. Concomitant use of rifampin or other potent inducers of CYP3A4 with ondansetron may result in a reduced antiemetic effect, particularly after oral administration of ondansetron.