Phase I and pharmacokinetic study of oral UFT, a combination of the 5-fluorouracil prodrug tegafur and uracil

UFT is an oral preparation combining the 5-fluorouracil (FU) prodrug tegafur (FT) and uracil (U) in a 1:4 ratio, which is commercially available in Japan for the treatment of breast and gastrointestinal cancers. We sought to determine the tolerance of daily oral UFT and to relate this tolerance to the pharmacokinetics of FT and/or the derived FU, while exploring the possibility of circadian FU kinetics contributing to the results. A 28-day schedule followed by 2 weeks rest was began at the initial level of 300 mg/m2/day administered either at 8 a.m. or at 6 p.m. At the following level, 400 mg/m2/day patients were randomly assigned to a split-dose administration or to the above single, timed dose administration. Intolerance to single dosing was clearly demonstrated, and only the split dosing was advanced to 500 mg/m2/day. When this level proved too toxic, 400 mg/m2 was studied further on a 7 a.m., 3 p.m., and 11 p.m. (every 8 h) schedule. Pharmacology was determined on selected patients. In the single dose administration, areas under the curves of FU were higher following p.m. dosing, although substantial interpatient variation was present. Toxicities (diarrhea and neutropenia) were more severe in patients receiving the drug in single daily doses. We conclude that the kinetics of FT are saturable, with disproportionate increases in area under the curve (and toxicities) as dose levels are increased. With divided dosing, tolerance improves. UFT at a dose of 400 mg/m2/day administered as three divided doses (every 8 h) is suitable for Phase II studies, although toxicity requiring cessation of drug administration prior to completion of 28-day cycles will occur in some patients.     

Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer

PURPOSE: This phase I study was performed to evaluate the safety and pharmacokinetics of escalating doses of Marimastat (British Biotech, Inc, Oxford, United Kingdom) in patients with advanced malignancies and to determine the phase II recommended dose to be used in subsequent studies. PATIENTS AND METHODS: A standard phase I design was used in this study, in which consecutive groups of three patients were treated with escalating doses of the study drug. Marimastat was administered orally at 25, 50, or 100 mg twice daily to consecutive groups of patients with advanced lung cancer. An additional three patients were added at the highest dose studied (100 mg orally twice daily) to assess whether the inflammatory polyarthitis observed at that dose level can be prevented by a concurrent administration of nonsteroidal antiinflammatory drugs (NSAIDS) and/or low-dose corticosteroids. Blood was drawn for safety monitoring, pharmacokinetic analysis, and plasma levels of metalloproteinase (MMP)-2 and MMP-9 (determined by zymography). A total of 12 patients were studied. RESULTS: The most significant toxicity at the highest dose studied (100 mg orally twice daily) was a symptomatic inflammatory polyarthritis that persisted for up to 8 weeks after discontinuation of the study drug and was dose-limiting. The estimated plasma elimination half-life of Marimastat was 4 to 5 hours. The mean maximum concentration (Cmax) at a reasonably well-tolerated dose (50 mg orally twice daily) was 196 ng/mL and was reached within 1 to 2 hours (Tmax) after administration. Areas under the curve (AUC) tended to correlate with the dose of Marimastat. Zymographic analysis of peripheral-blood ratios of activated proenzymatic forms of MMP-2 and -9 did not show any consistent patterns of change in MMP levels or in a degree of their activation during the course of treatment. CONCLUSION: Marimastat was well absorbed from the gastrointestinal tract, with high levels of the study drug detected in plasma within hours after drug administration. Plasma concentrations of Marimastat achieved at dose levels 2 and 3 (50 mg and 100 mg orally twice daily) were substantially higher than those required for MMP inhibition in vitro. The dose-limiting toxicity (DLT) was severe inflammatory polyarthritis, which seemed to be a cumulative toxicity.     

A phase I dose-ranging safety and pharmacokinetics study of a novel oral thromboxane synthase inhibitor, FCE 22, 178

A 100- to 3200-mg dose range of FCE 22,178 was studied in this phase I single-dose escalation safety/kinetics study. After oral administration, a rapid drug absorptive phase and a biexponential disposition profile were observed. Mean estimates of the terminal elimination half-life of FCE 22,178, over the doses studied, ranged from 7.6 to 14.4 hours. A disproportionate increase in both maximum peak plasma concentration (Cmax) and area under the curve (AUC0-infinity) was noticed for doses higher than 400 mg. Mean estimates of systemic clearance (CLs/F) over the 100- to 400-mg doses were 0.053 to 0.064 L/hour/kg, and were significantly higher for the three higher dose levels. This nonlinearity appears to be related to the changes in oral bioavailability. Estimates of distribution volume (Vd, lambda z/F) for FCE 22,178 increased from 0.75 L/kg at the 100-mg dose to 3.00 L/kg at the 3200-mg dose, and renal clearance (CLr) also increased with dose. Both observations may be related to an increase in free fraction of FCE 22,178 at higher doses. Urinary excretion of unchanged drug averaged < 10% for all dose levels. The urinary excretion of the glucuronide metabolite (M1) averaged 41 to 70% for doses up to 400 mg, but diminished to 13% at the 3200-mg dose. The disposition of M1 appeared to be formation-rate limited. In addition, the ratio of the formation to the disposition clearance for M1 was relatively stable and apparently dose independent. No drug-related adverse experiences were observed over the studied dose range after single doses at FCE 22,178.     

Tolerance development to cadmium-induced alteration of drug action

Cadmium administration potentiates the duration of hexobarbital-induced hypnosis and inhibits the rate of hepatic microsomal metabolism of this drug in the male rat. The threshold dose of cadmium required to produce these alterations in drug action is 0.84 mg Ck/kg. If subthreshold doses of cadmium (0.21 or 0.42 mg Cd/kg) are administered prior to the 0.84 mg Cd/kg dose, the cadmium-induced alterations in drug action are no longer observed.     

Preoperative autologous donation of 6 units of blood during rh-EPO treatment

Once daily administration of Lantana camara leaves juice at different dose levels (60, 300, 600 and 1500 mg/kg/day) for 14 days in rats resulted in alterations in various haemato- and biochemical parameters. Significant increase in blood urea nitrogen was observed with the doses of 600 and 1500 mg while significant increase in the relative weights of adrenals was observed at all the four dose levels. Total proteins, globulins, absolute lymphocyte count and per cent lymphocyte count were significantly decreased with 60, 600 and 1500 mg doses while a significant hypoglycemic effect was observed with 1500 mg only. Rats treated with 1500 mg dose did not exhibit any increase in alanine aminotransferase and aspartate aminotransferase activities or the alterations in relative kidney and liver weights. In another set of experiment, once daily oral administration of 1500 mg/kg/day for 14 days significantly inhibited the granulomatous tissue formation in rats and this effect was comparable to that of cyclophosphamide (10 mg/kg/day).     

Inverse nonlinear pharmacokinetics of total and protein unbound drug (oxaprozin): clinical and pharmacokinetic implications

The nonsteroidal antiinflammatory drug oxaprozin is extensively bound to plasma proteins in a concentration-dependent manner. This study demonstrates for the first time the inverse nonlinear pharmacokinetics of total and unbound oxaprozin and presents clinical implications of this phenomenon. A total of 71 healthy volunteers participated in single- and multiple-dose studies. In study I, 0.6-, 1.2-, and 1.8-gm doses of oxaprozin were given on an empty stomach in a randomized, crossover trial (n = 35). In studies II and III, 1.2- and 1.8-gm doses, respectively, were given once a day for 8 days (n = 12 and 24, respectively). Serial blood samples for total and unbound drug assays were taken over a 240-hour period in study I and for a 24-hour period on days 1, 5, and 8 in studies II and III. After administration of 1.2 gm once daily, steady-state conditions were established by day 5. Actual average steady-state plasma concentrations (Cavg) were lower than those predicted from the single-dose study based on linear kinetics for the total drug, but higher for the unbound drug. Nonlinear changes in Vd/F were also noted with multiple-dose administration. Vd/F increased by 47% for total drug but decreased by 61% for unbound drug relative to single-dose values. Half-lives after single-dose administration for total and unbound drug determined from 24 to 240 hours and from 24 to 72 hours, respectively, were dose independent for total drug, but dose dependent for unbound drug. Half-lives after multiple-dose administration measured from 24 to 48 hours in study II decreased further. In conclusion, oxaprozin clearance for the total drug was increased while that of the unbound drug was decreased after repetitive dosing. This inverse pharmacokinetic behavior has been attributed to the two noncompensatory kinetic effects: concentration-dependent protein binding and saturable metabolism of oxaprozin.     

The relationship between the degree of neurodegeneration of rat brain 5-HT nerve terminals and the dose and frequency of administration of MDMA ('ecstasy')

The effect of varying the dose and frequency of administration of 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') on both the acute hyperthermic response and the long term neurodegeneration of 5-hydroxytryptamine (5-HT) nerve terminals in the brain has been studied in Dark Agouti rats. A single injection (4-15 mg/kg i.p.) of MDMA produced immediate dose-related hyperthermia and a dose-related decrease in 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and [3H]paroxetine binding in regions of the brain 7 days later, with a dose of 4 mg/kg having no degenerative effect. This dose was also without effect when given once daily for 4 days, but produced a marked loss of [3H]paroxetine binding and indole concentration ( approximately 55%) when given twice daily for 4 days. When a dose of 4 mg/kg was given twice weekly for 8 weeks it had no effect on these serotoninergic markers, despite a clear anorectic effect of the drug being seen. These data demonstrate that MDMA-induced neurodegeneration is related to both the dose and frequency of administration and indicate that damage to 5-HT neurones can occur in the absence of a hyperthermic response to the drug. We suggest that damage occurs when endogenous free radical scavenging mechanisms become overwhelmed or exhausted.     

Clinical pharmacokinetics of oxaprozin

Oxaprozin is a nonsteroidal anti-inflammatory drug which reaches peak plasma concentrations 2 to 6 hours after oral administration. Oxaprozin binds extensively, in a concentration-dependent manner, to plasma albumin. The area under the plasma concentration-time curve (AUC) of oxaprozin is linearly proportional to the dose for oral doses up to 1200 mg. At doses greater than 1200 mg there is an increase in the unbound fraction of drug, leading to an increased clearance and volume of distribution (Vd) of total oxaprozin. Accumulation of the drug at steady state is between 40 and 58% lower than predicted by single dose data. After administration of multiple doses, the apparent oral clearance (CL/F) and Vd of total oxaprozin increased while those of the unbound drug decreased significantly. Substantial concentrations of oxaprozin are attained in synovial fluid, which is a proposed site of action for nonsteroidal anti-inflammatory drugs. Relationships between total plasma, unbound plasma and synovial concentrations, and therapeutic and toxicological effects have yet to be established. Oxaprozin is eliminated following biotransformation to glucuroconjugated metabolites which are excreted in urine and bile, with little drug being eliminated unchanged. Two hydroxylated metabolites have been shown to possess anti-inflammatory activity. Hepatic disease and rheumatoid arthritis do not significantly alter the disposition of oxaprozin. Patients with renal impairment demonstrate an increase in unbound plasma concentrations of oxaprozin. A significant drug interaction has been demonstrated between oxaprozin and aspirin (acetylsalicylic acid).     

Treatment of hypothyroidism with once weekly thyroxine

We compared daily T4 therapy with 7 times the normal daily dose administered once weekly in 12 hypothyroid subjects in a randomized cross-over trial. At the end of each treatment we measured serum free T4 (FT4), free T3 (FT3), rT3, and TSH levels and multiple markers of thyroid hormone effects at the tissue level repeatedly for 24 h. Compared with daily administration, the mean serum TSH before the administration of weekly T4 was higher (weekly, 6.61; daily, 3.92 microIU/mL; P < 0.0001), and the mean FT4 (weekly, 0.98; daily, 1.35 ng/dL; P < 0.01) and FT3 (weekly, 208, daily, 242 pg/dL; P < 0.01) were lower. A minimally elevated serum total cholesterol during weekly administration (weekly, 246.8; daily, 232.6 mg/dL; P < 0.03) was the only evidence of hypothyroidism at the tissue level. Compared with daily administration, the mean peak FT4 following weekly administration of T4 was significantly higher (weekly, 2.71; daily, 1.59 ng/dL; P < 0.0001), as was the mean peak FT3 level (weekly, 285; daily, 246 pg/dL; P < 0.01). None of the tissue markers of thyroid hormone effect changed compared to daily T4, and there was no evidence of treatment toxicity, including cardiac toxicity. During weekly T4 administration, autoregulatory mechanisms maintain near-euthyroidism. For complete biochemical euthyroidism a slightly larger dose than 7 times the normal daily dose may be required.     

Dopamine-secreting glomus vagale: a case report and histopathologic correlation

The effect of atorvastatin, a CYP3A4 substrate, on the pharmacokinetics of terfenadine and its carboxylic acid metabolite, fexofenadine, were evaluated. Single 120-mg doses of terfenadine were given 2 weeks apart to healthy volunteers with 80-mg daily doses of atorvastatin administered from 7 days before through 2 days after the second terfenadine dose. Concentrations of terfenadine and fexofenadine were measured for 72 hours after each terfenadine dose. Administration of terfenadine alone or in combination with atorvastatin produced no alterations in the QTc interval. For terfenadine, atorvastatin coadministration produced an 8% decrease in maximum concentration (Cmax), a 35% increase in area under the concentration-time curve extrapolated to infinity (AUC0-infinity), and a 2% decrease in elimination half-life (t1/2). For fexofenadine, atorvastatin coadministration produced a 16% decrease in Cmax, a 2% decrease in AUC0-infinity and a 51 % increase in t1/2. None of these changes achieved statistical significance. Coadministration of atorvastatin with terfenadine does not result in a clinically significant drug interaction. Because 80 mg is the highest atorvastatin dose used clinically, drug interactions mediated by CYP3A4 inhibition are unlikely in clinical practice.     

Ocular pharmacokinetics of orally administered azithromycin in rabbits

Azithromycin was orally administered to Dutch-belted rabbits following extracapsular lens extraction in one eye. At various times the animals were sacrificed, and serum and ocular tissues were obtained for drug level determination by HPLC-EC. Following a single dose, peak levels of drug in ocular tissues were measured within 8 hours (cornea > 0.5 micrograms/g [15mg/kg]; > 1.5 micrograms/g [3Omg/kg]). Highest levels were obtained in iris and ciliary body ( > 15 micrograms). Measurable tissue levels persisted for at least 120 hours. Trough levels increased proportionately during drug multiple dose administration. Five days following five daily 15mg/kg doses, corneal levels exceeded 0.5 micrograms/g, and iris and ciliary levels were higher than 15 micrograms/g. Aqueous humor and serum levels were equivalent. Vitreous humor levels, though higher than aqueous humor, were consistently < 1 microgram/ml. Extracapsular cataract extraction did not significantly affect drug uptake.     

Murine and human in vivo penclomedine metabolism

Penclomedine is a multichlorinated alpha-picoline derivative which has shown prominent activity in murine breast cancer models and is currently undergoing clinical development. Previous in vitro research has identified several penclomedine metabolites. In this study, human and murine in vivo penclomedine metabolism was examined. Upon i.v. administration to mice, no penclomedine was detectable in plasma at time points as early as 1 h postinfusion. The principle metabolite was demethyl-penclomedine [3, 5-dichloro-2-methoxy-4-hydroxy-6-(trichloromethyl)pyridine]. Both penclomedine and demethyl-penclomedine could be recovered from tissues. Greater than 60% of the penclomedine dose remaining in the body at 22 h was indelibly bound to tissue and plasma proteins. Urinary metabolites of penclomedine consisted mainly of penclomic acid and additional polar metabolites. The results obtained after p. o. administration were nearly identical to i.v. administration with respect to the extent, level, and type of metabolites found in the plasma, tissues, and urine and with respect to the extent of protein binding. In human subjects administered penclomedine daily for 5 consecutive days, demethyl-penclomedine could be detected in plasma and accumulated with successive doses of penclomedine, reaching peak plasma concentrations of up to 10 times that of penclomedine itself and plasma exposures of nearly 400 times that of the parent drug. It appears that patients eliminate penclomedine largely through metabolism and that this drug may be amenable to p.o. administration.     

Carcinoid to cecal bowel localization: a case report and literature review

Data are submitted from long-term follow-ups over 78 patients with Gilbert-Meylengraht's syndrome (71 men and 7 women). The above syndrome was identifiable predominantly in those persons aged 15-30. A major proportion of the patients (75%) displayed different dyspeptic phenomena and asthenovegetative disturbances, 25% had no complaints. The principle diagnostic criterion for the syndrome is predominant or solitary elevation of blood serum levels of free (unconjugated, indirect) bilirubin without signs of affection liver, obturation of the biliary tract, and enhanced hemolysis. This form hyper bilirubinemia runs benign course. All above patients remain able bodied having enough capacity for work. In exacerbations, it is helpful to prescribe small doses of phenobarbital (0.05-0.15 gr daily), under the influence of which drug the serum level of bilirubin returns to normal, this effect lasting only for a period of the drug administration.     

Pharmacokinetics of meloxicam in patients with end-stage renal failure on haemodialysis: a comparison with healthy volunteers

OBJECTIVE: The pharmacokinetics of meloxicam have been studied following administration of a single 15-mg capsule to 12 patients with end-stage renal failure. Pharmacokinetic parameters were determined after haemodialysis. The pharmacokinetic profile obtained in these patients is compared to data obtained from age- and gender-matched healthy volunteers. RESULTS: Total plasma meloxicam concentrations were lower in patients with end-stage renal failure (AUC0-infinity 12.6 micrograms.h.ml-1) in comparison with healthy volunteers (AUC0-infinity 39.3 micrograms.h.ml-1). This was reflected by an increase in total clearance (+211%). However, there was an enhanced free meloxicam fraction (unbound drug) in the end-stage renal failure patients (0.9% vs. 0.3% in healthy volunteers). This was observed in association with raised free Cmax (5.0 vs. 2.6 ng/ml) but similar free AUC0-infinity (0.13 vs. 0.11 microgram.h.ml-1) in both groups. Therefore, the raised free fraction is compensated for by the increased total clearance such that no accumulation of meloxicam occurs. Meloxicam plasma concentrations were similar before and after haemodialysis. CONCLUSION: Meloxicam has displayed a pharmacokinetic profile in end-stage renal failure which is similar to that observed for other highly protein bound nonsteroidal anti-inflammatory drugs (NSAIDs). However, in view of the higher free Cmax value, and despite no evidence of accumulation, it may be prudent to treat this group of patients with a 7.5-mg dose of meloxicam. This is the lower dose normally recommended for adults. Meloxicam is not dialysable.     

Effect of liposomal methylprednisolone on heart allograft survival and immune function in rats

Liposomal methylprednisolone (L-MPL) applied in monotherapy prolonged cardiac allograft survival in rats in comparison with the same dosage regimen of drug in solution (Solu-Medrol). The most efficacious treatment consisted of a 2-mg/kg i.v. dose of L-MPL twice a week (group III), producing survival up to 30 days, followed by a 4-mg/kg/week dose of L-MPL (group IV) and a single 2-mg/kg dose of L-MPL (group II). Survival in animals receiving Solu-Medrol as a 2-mg/kg dose twice a week (group V) did not differ from untreated animals. Only daily 4-mg/kg doses of methylprednisolone (MPL) in solution (group VI) were as effective as group III. The concentrations of MPL in liver and spleen were detectable for 26 days after the last dose of L-MPL, showing tissue selective sequestration of drug. Treatment at these low doses did not suppress endogenous corticosterone determined 24 hr or later in plasma. The administration of steroid caused significant immunosuppression in most animals as measured by inhibition of splenocyte blastogenesis induced with phytohemagglutinin. Cellular immunity data did not differ significantly between groups, but alterations occurred at day 14 to 15 after surgery: CD3, CD4 and ratio CD4:CD8 subsets of cells showed minimum values; CD8, CD4CD8, CD25 and white blood cell counts were at maximum at this time. Slight but significant differences between Immunoglobulin M suppression in group II compared to group I or V were found, whereas Immunoglobulin G values were unchanged. The transplantation and treatment with steroid decreased the total body weight of animals but increased weights of internal organs, particularly spleen, similarly for all groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (+/- standard deviation) in the children was 0.53 +/- 0.19 liter/kg/h (229 +/- 77 ml/min/m2 of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 +/- 0.18 and 2.2 +/- 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% +/- 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 microM for >/=8 h of 24 h on the twice daily oral dosing schedule with doses of >/=2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.     

Intravenous propranolol administration: a method for rapidly achieving and sustaining desired plasma levels

A model for the intravenous administration of propranolol by a bolus-infusion technique designed to rapidly produce, then maintain, predicted plasma drug concentrations was derived from elimination kinetics in single-dose studies. Prospective testing of this model in 6 adult male subjects revealed a close correlation between predicted and observed drug levels; desired plasma concentrations were achieved within 5 min and maintained over the 30-min study period. By subtracting previously given bolus doses from the dose calculated as needed to produce a desired plasma level, progressive increases in predicted propranolol levels could be effected, with apparent maintenance of equilibrium. Correlations between the bolus doses and infusion rates and the plasma drug levels were consistent and significant, and constitute nomograms from which the dose of drug required to produce a desired plasma level may be approximated. The clearance of propranolol declined slightly as the drug plasma level increased, but did not significantly affect the accuracy of the model.     

Two groups of endogenous MMTV related retroviral env transcripts expressed in human tissues

Object exploration was examined in naloxone injected (1 mg/kg or 4 mg/kg) and saline control rats. Naloxone rats explored an object for a shorter time than did controls, thus indicating a lower investigatory motivation. This effect was dose dependent. Higher drug dose (4 mg/kg) decreased the number of contacts with an object. Both doses increased the mean duration of contacts with an object. The naloxone groups showed intact recognition of a familiar object paired with a new one in two sessions--4 h and 24 h after the injections. The higher drug dose depressed the locomotor activity and wall leaning. Grooming was not influenced by naloxone. The normal daily fluctuations in the level of grooming and locomotion were distorted following the injection of the higher dose of naloxone. The lower dose (1 mg/kg) did not affect the rats' performance in some tests. The results could be viewed as a naloxone-related depression of the behavior containing motor elements like locomotion, wall leaning and object approaching. The prolonged contact time with an object could be the result of a lowered flexibility of movement. However, the decrease of rewarding value of exploration could not be ruled out. Possibly, naloxone exerts several different interacting behavioral effects.     

Road traffic mortality in Victoria: an exploratory investigation into successful strategies

The recovery of radioactivity from plasma, urine and feces was determined in rats after administration of oral and intravenous doses (200 mg/kg) of 14C-labeled sodium gamma-hydroxybutyric acid. Very small portions of the radioactive dose were recovered in the urine (5.5%, oral; 7.1%, intravenous) and feces (1.5% oral; 0.6%, intravenous) collected between 0-48 hours after drug administration. Considerable levels of radioactivity were found in the plasma after oral dosing. The area under the plasma radioactivity time curve after an oral dose was found to be 65% of that observed after an equivalent intravenous dose. This value is much larger than the relative area value (8%) calculated on the basis of free gamma-hydroxybutyric acid. Results of this study strongly indicate that first-pass metabolism, rather than lack of absorption, is responsible for the apparently poor oral bioavailability of gamma-hydroxybutyric acid.     

Role of experience in acquisition and loss of tolerance to the effect of delta-9-THC on spaced responding

Albino rats were given extensive training in spaced responding, using a DRL 30 sec schedule of food reinforcement (only lever presses more than 30 sec apart were reinforced). All rats then went 12 days without behavioral testing. During this period half the rats received daily intragastric doses of delta-9-tetrahydrocannabinol (THC) and the rest equal volumes of the THC vehicle. On day 13, some rats received THC 3 hr before behavioral testing while others received only vehicle. The former showed a sharp increase in lever press rate over baseline levels, but the vehicle control rats were unaffected. The rats with 12 prior THC doses were no less affected than those with no previous drug history. Continued testing resulted in recovery of baseline performance within 5 sessions, again with no effect of previous drug history. Similar results were obtained with doses of 4 mg/kg and 16 mg/kg, though the drug's effects were more pronounced at the higher dose. These results demonstrate that performance in the drug state can be a far more important determinant of tolerance than mere exposure to THC. Drug administration was then suspended for 1 week. Rats that had become tolerant to 4 mg/kg THC were then redivided into 3 new groups. One group received daily doses of vehicle and DRL sessions, a second received DRL sessions without vehicle, and 1 group received neither vehicle nor DRL sessions for this week. Subsequent DRL testing after THC administration showed that only the groups receiving DRL sessions in the intervening week lost their previously acquired tolerance. Experience thus appears to play an important role in loss of tolerance to THC as well as in acquisition of tolerance.