The role of Gilbert's syndrome and frequent NAT2 slow acetylation polymorphisms in the pharmacokinetics of retigabine.

Retigabine (RGB) is an investigational antiepileptic drug, which undergoes extensive UGT1A1, 1A9 and 1A4-mediated N-glucuronidation and N-acetylation. The mono-acetylated metabolite of RGB has some pharmacological activity and is denoted AWD21-360. We investigated whether the pharmacokinetics (PK) of RGB and AWD21-360 are altered in subjects with Gilbert's syndrome (GS) and/or with frequent N-acetyltransferase 2 (NAT2) slow acetylator (SA) polymorphisms. Based on consistent genotyping and phenotyping screening results, 37 Caucasian subjects (21-46 years; 31 men, six women) were assigned to one of the following groups: (1) absence of GS (non-GS)/rapid acetylator (RA) (N=11); (2) GS/RA (N=8); (3) non-GS/SA (N=11); (4) GS/SA (N=7). Subjects received single and multiple (b.i.d.) 200-mg oral RGB doses over 5 days. Blood samples were collected up to 60 h after dosing for plasma PK of RGB and AWD21-360. Group comparisons were performed by ANOVA. Single-dose PK of RGB and AWD21-360 and multiple-dose PK of RGB did not differ significantly between groups. After multiple dose treatment, RA subjects showed a significantly higher total exposure to AWD21-360 of about 32% (95% CI 101.9-172.5) relative to SA subjects (P=0.0362). The UGT1A1 metabolic capacity (i.e. presence or absence of GS), however, did not significantly affect the overall exposure to AWD21-360. The results indicate that the PK of RGB is unaltered in individuals with GS, in subjects with NAT2 SA status, and in carriers of both variants, whereas the total exposure to AWD21-360 is significantly related to the RA or SA status of subjects. Results further suggest that metabolic switching to the mono-acetylated metabolite AWD21-360 may partially compensate for the impaired glucuronidation capacity in GS subjects. RGB treatment showed no significant differences in tolerability and safety between groups.

Plasma and follicular fluid concentrations of LHRH antagonist cetrorelix (Cetrotide) in controlled ovarian stimulation for IVF.

Cetrorelix was administered in differing daily dosages for controlled ovarian stimulation. The dosage levels were 3 mg (9 cycles), 1 mg (19 cycles), 0.5 mg (43 cycles), 0.25 mg (46 cycles) and 0.1 mg (7 cycles). In the 3 mg, 1 mg and 0.5 mg group the respective median plasma concentrations of cetrorelix on the day of oocyte pick-up (OPU) were 2.10 ng/ml, 1.42 ng/ml and 0.88 ng/ml and 1.03 ng/ml, 0.46 ng/ml and 0.49 ng/ml on the day of embryo transfer (ET). In the 0.25 mg and 0.1 mg groups plasma cetrorelix levels were below the limit of quantification. The cetrorelix concentrations in follicular fluid (FF) in the 0.25 mg group were detectable in only 14 out of 44 samples, while in the 0.1 mg group no detectable concentrations could be obtained. We also examined 80 cycles after single doses of 5 mg (7 cycles), 3 mg (42 cycles), and 2 mg (31 cycles) cetrorelix. On the day of OPU the respective median plasma concentrations of cetrorelix were 0.57 ng/ml, 0.62 ng/ml, and 0.56 ng/ml, and 0.61 ng/ml and 0.28 ng/ml on the day of ET in the 5 mg and 3 mg groups. In the 2 mg group, the plasma concentrations fell to below limits of quantification in 8/9 samples on the day of ET. In 26 out of 27 FF samples cetrorelix was detectable in the 3 mg single dose group (median level: 0.69 ng/ml).

Phase I trial of 6-hour infusion of glufosfamide, a new alkylating agent with potentially enhanced selectivity for tumors that overexpress transmembrane glucose transporters: a study of the European Organization for Research and Treatment of Cancer Early Clinical Studies Group.

PURPOSE: To determine the maximum-tolerated dose (MTD), the principal toxicities, and the pharmacokinetics of 6-hour infusion of glufosfamide (beta-D-glucosylisophosphoramide mustard; D-19575), a novel alkylating agent with the potential to target the glucose transporter system. PATIENTS AND METHODS: Twenty-one patients (10 women and 11 men; median age, 56 years) with refractory solid tumors were treated with doses ranging from 800 to 6,000 mg/m(2). Glufosfamide was administered every 3 weeks as a two-step (fast/slow) intravenous infusion over a 6-hour period. All patients underwent pharmacokinetic sampling at the first course. RESULTS: The MTD was 6,000 mg/m(2). At this dose, two of six patients developed a reversible, dose-limiting renal tubular acidosis and a slight increase in serum creatinine the week after the second and third courses of treatment, respectively, whereas three of six patients experienced short-lived grade 4 neutropenia/leukopenia. Other side effects were generally mild. Pharmacokinetics indicated linearity of area under the time-versus-concentration curve against dose over the dose range studied and a short elimination half-life. There was clear evidence of antitumor activity, with a long-lasting complete response of an advanced pancreatic adenocarcinoma and minor tumor shrinkage of two refractory colon carcinomas and one heavily pretreated breast cancer. CONCLUSION: The principal toxicity of 6-hour infusion of glufosfamide is reversible renal tubular acidosis, the MTD is 6,000 mg/m(2), and the recommended phase II dose is 4, 500 mg/m(2). Close monitoring of serum potassium and creatinine levels is suggested for patients receiving glufosfamide for early detection of possible renal toxicity. Evidence of antitumor activity in resistant carcinomas warrants further clinical exploration of glufosfamide in phase II studies.

Pharmacokinetic and pharmacodynamic modeling of cetrorelix, an LH-RH antagonist, after subcutaneous administration in healthy premenopausal women.

PURPOSE: The purpose of this study was the development of pharmacokinetic and pharmacodynamic models for the luteinizing hormone (LH) suppression and subsequent shift in LH surge and follicle-stimulating hormone by cetrorelix in women. BACKGROUND: Cetrorelix is a potent luteinizing hormone-releasing hormone (LH-RH) antagonist and is used for the prevention of the premature ovulation indicated by an LH surge in in vitro fertilization. The pharmacokinetic and pharmacodynamic relationship for the suppression and the shift in the LH surge has not yet been established. METHODS: In a placebo-controlled study, single subcutaneous doses of 1, 3, and 5 mg of cetrorelix were given to 36 subjects on day 8 of the natural menstrual cycle. Cetrorelix, LH, follicle-stimulating hormone, estradiol, and progesterone were determined. RESULTS: Cetrorelix pharmacokinetics were described by a 2-compartment model with a terminal half-life of 56.9 +/- 27.1 hours. Mean shift in LH surge was by 4.1, 7.5, and 9.3 days with the 1-, 3-, and 5-mg doses, respectively. An indirect response sigmoid Emax model was developed for the suppression of LH and the shift in the LH surge. The inhibitory concentration of 50% (for LH suppression) and median effective concentration (for surge shift) estimates were 3.6 ng/mL and 1.6 ng/mL, respectively. The suppression of follicle-stimulating hormone was described by a similar Emax model, with an inhibitory concentration of 50% of 7.25 ng/mL. CONCLUSIONS: A pharmacokinetic and pharmacodynamic model was developed for the transient initial suppression of LH and the subsequent shift in the LH surge after 3 single subcutaneous doses of cetrorelix without ovarian stimulation. A separate model was developed for the suppression of follicle-stimulating hormone by cetrorelix. The shift in the LH surge could be adequately described by the model.

Dose-proportionality of oral thioctic acid--coincidence of assessments via pooled plasma and individual data.

Thioctic acid (TA), a racemate of R-(+)- and S-(-)-enantiomers of alpha-lipoic acid, acts as a powerful lipophilic, free-radical scavenger and is used in the treatment of diabetic neuropathy. This trial investigated the dose-linearity of enantiomer pharmacokinetics following the oral administration of single doses of 50 to 600 mg TA (formulation provided by ASTA (Medica)) in healthy volunteers. TA enantiomer concentrations in individual and pooled plasma samples were determined using enantioselective, high-performance liquid chromatography. TA was rapidly absorbed (tmax, 0.5 to 1 h). Maximum plasma concentrations (Cmax) of the R-(+)-enantiomer were about 40-50% higher than those of the S-(-)-enantiomer (50 mg: 135.45 ng/ml R-(+)-TA, 67.83 ng/ml S-(-)-TA; 600 mg: 1812.32 ng/ml R-(+)-TA, 978.20 ng/ml S-(-)-TA; geometric means). The decline observed in the plasma concentration was steep (t1/2, 0.5 h). The dose-linearity and proportionality of pharmacokinetic parameters could be demonstrated on an intra-individual basis and for the group geometric means. An analysis of pooled plasma samples proved to be a suitable means for deriving reliable first-sight results prior to individual assessments.

Single and multiple dose pharmacokinetics and pharmacodynamics of the gonadotrophin-releasing hormone antagonist Cetrorelix in healthy female volunteers.

The gonadotrophin-releasing hormone antagonist Cetrorelix is in advanced clinical development for the control of endogenous gonadotrophin secretion during the course of a fertility programme. The aim of the present study was to investigate the pharmacokinetics and pharmacodynamics of Cetrorelix following single and multiple s.c. administration of different doses. Thirty-six healthy female volunteers received either 0.25, 0.50 or 1.00 mg Cetrorelix, in a first menstrual cycle as single dose and in a second cycle as multiple dose (daily between cycle days 3 and 16). Frequent blood samples were collected for determination of Cetrorelix, follicle stimulating hormone (FSH), luteinizing hormone (LH), oestradiol and progesterone concentrations. Follicular growth was measured by transvaginal ultrasonography. After single administration of each dose, maximum Cetrorelix concentrations (Cmax) were reached after 1 h, and Cmax and area under curve (AUC) increased linearly with the dose. The median terminal half-life ranged from 5 to 10 h in the three different dose groups. FSH, LH, oestradiol and progesterone concentrations were suppressed, with a nadir at 6-12 h after Cetrorelix administration. During multiple administration, Cmax and AUC also showed dose-linearity. The median terminal half-life of Cetrorelix varied between 20 and 80 h. A dose-dependent suppression of FSH, LH and oestradiol concentrations was observed during treatment. After multiple administration, ovulation was delayed for 5, 10 and 13 days in the 0.25, 0.50 and 1.00 mg dose groups, respectively. In conclusion, Cetrorelix showed linear pharmacokinetics, and effectively delayed the LH surge.

Gastric emptying in patients with insulin dependent diabetes mellitus and bioavailability of thioctic acid-enantiomers.

The objective of this study was to determine the impact of prolonged gastric emptying in patients with insulin dependent diabetes mellitus (IDDM) on the bioavailability of the R(+)- and S(-)-thioctic acid (TA) enantiomers. Gastric emptying time (GET) was assessed in 30 healthy volunteers and 22 patients with IDDM using sequential ultrasonography after a standardized solid-liquid test meal. Pharmacokinetics and absolute bioavailability (F) of the TA-enantiomers were studied using a randomized, open two-way crossover design with administrations of oral and intravenous single doses of 200 mg rac-TA. GET in healthy subjects was 134.7+/-21.6 min, the normal range was calculated from 88.3 to 181.1 min. The mean GET in all IDDM patients was significantly prolonged (178.2+/-28.1 min; P<0.001). Only 50% of the patients (n=11) were found to have normal GET (group A), the other half of the population (n=11) were considered to have delayed GET (group B). Mean GET values were 156.9+/-21.5 in group A (P=0.028) and 199.4+/-13.9 min in group B, respectively, suggesting that gastric motility is significantly different from non-diabetic controls even in patients with apparently normal gastric emptying. Times to peak plasma concentrations (t(max)) of both TA-enantiomers were similar in both groups and thus, unrelated to measures of gastric emptying. In contrast, maximum concentrations (C(max)) and area-under-the-curve values (AUC) of both enantiomers were reduced by about 30% in patients with delayed GET. Although these differences resulted in statistical significance for the AUC of both enantiomers (P<0.05), linear regression analysis showed only modest correlation between GET and the extent of TA-enantiomer absorption (r2=0.31 and 0.22 for R(+)-/S(-)-TA, respectively). The study suggests that prolonged gastric emptying is frequently present in IDDM. Delayed gastric emptying, however, does not substantially affect the rate and extent of absorption of both TA-enantiomers.

Enantioselective high-performance liquid chromatography assay of (+)R- and (-)S-alpha-lipoic acid in human plasma.

A specific plasma level assay for the enantiomers of alpha-lipoic acid is described. It makes use of liquid-liquid extraction, chemical reduction to the dithiol enantiomers, and their precolumn chiral derivatisation with o-phthalaldehyde in the presence of D-phenylalanine. The two diastereomeric derivatives are separated by reversed-phase HPLC with fluorescence detection. The working range of the assay is between 15 ng/ml (lower limit of quantitation) and 1,000 ng/ml for either enantiomer.

Clinical phase I and pharmacokinetic trial of the new titanium complex budotitane.

Budotitane [cis-diethoxybis(1-phenylbutane-1,3-dionato)titanium (IV)] is a novel inorganic metal complex. Preclinical studies in established screening models indicate considerable antitumor activity. We have performed a clinical Phase I and pharmacokinetic trial with budotitane administered as i.v. infusion twice weekly. The starting dose of 100 mg/m2 was derived from a prior single dose Phase I study. Eighteen patients with solid tumors refractory to all other known treatment modalities were entered. 17 patients had received prior chemotherapy. Dose levels ranged from 100 mg/m2 to 230 mg/m2, with a total of 122 budotitane infusions administered. Neither leuko- nor thrombocytopenia were observed. 2/5 pts at 180 mg/m2 and 2/4 pts at 230 mg/m2 developed a 3-fold increase of reticulocytes without signs of hemolysis or bleeding. Nonhematologic toxicity was moderate at doses of < or = 180 mg/m2. Fifteen patients reported loss of taste at the day of infusion. At 230 mg/m2, 2/4 pts developed WHO grade 3 cardiac arrhythmias with polytope premature ventricular beats and nonsustained ventricular tachycardia. A limited pharmacokinetic analysis was performed at dose levels 180 mg/m2 and 230 mg/m2. At 180 mg/m2, Cmax was 2.9 +/- 1.2 microg/ml, t1/2 78.7 +/- 24.4 h, Cltot 25.3 +/- 4.6 ml/min and AUC 203 +/- 71.5 h x microg/ml. At 230 mg/m2, Cmax was 2.2 +/- 0.8 microg/ml, t1/2 59.3 +/- 12.1 h, Cltot 44.9 +/- 23.6 ml/min and AUC was 183 +/- 90.4 h x microg/ml. No objective tumor response was observed. We conclude that the maximum tolerated dose of budotitane administered twice weekly is 230 mg/m2, the dose limiting toxicity is cardiac arrhythmia. Further evaluation of the nature of the cardiac toxicities observed is warranted. Using this schedule, 180 mg/m2 is a safe dose for subsequent clinical studies.

Pharmacokinetics of naftopidil, a novel anti-hypertensive drug, in patients with hepatic dysfunction.

The pharmacokinetics of naftopidil, a novel alpha-1 adrenoceptor-blocking antihypertensive, were investigated in ten patients (9M/1F) with hepatic dysfunction after oral administration (50 mg, tablet) and after an intravenous infusion of 5.0 mg over 2 minutes. Results were compared to a control group of 12 healthy subjects (6M/6F) of a previous investigation, which was carried out according to the identical study protocol. The pharmacokinetic parameters obtained for the i.v. administration were comparable in both groups (half life 3.6 +/- 3.4 hours in liver-impaired subjects versus 3.3 +/- 2.1 hours in controls; clearance 11.9 +/- 4.7 ml/minute/kg versus 11.0 +/- 1.6 ml/minute/kg). Following oral administration the plasma levels and half-life times of naftopidil were significantly increased in liver impairment (t1/2 16.6 +/- 19.3 hours versus 5.4 +/- 3.2 hours in controls; P = 0.012). Mean values for the absolute bioavailability in patients with hepatic dysfunction were significantly higher (mean 75%, median 53%, range 13.4-211.0%) compared to healthy subjects (mean 17%, median 16%, range 6.7-29.6%, P = 0.001). Reduction of functional hepatic blood flow in chronic liver disease or, as evidenced in one case as a consequence of shunt surgery, is the probable cause of the observed alteration in naftopidil kinetics. This phenomenon occurred only following the oral 50 mg dose whereas the intravenous 5 mg dose obviously still could be normally handled. Naftopidil demethylation and hydroxylation were both less and non-uniformly affected. The pharmacokinetic findings suggest that in patients with severe hepatic impairment or evidence for marked changes in hepatic blood flow the dose of naftopidil may require adjustment to the lower end of the therapeutic range and/or may be limited to once daily. However, before definite conclusions can be drawn, further steady-state studies are required. Despite the pharmacokinetic discrepancies no difference in drug tolerability was seen between patients and healthy subjects.

Naftopidil inhibits 5-hydroxytryptamine-induced platelet aggregation and 5-hydroxytryptamine uptake in platelets of healthy volunteers.

Naftopidil exerts its antihypertensive action via alpha 1-adrenoceptor blockage and Ca2+ antagonism in vascular smooth muscle. Since the chemically similar 1-(1-naphthyl) piperazine is known to be a 5-hydroxytryptamine2 receptor antagonist, the 5-hydroxytryptamine (5-HT) antagonistic properties of naftopidil were tested by examining 5-HT-induced aggregation and 5-HT uptake in platelets from 12 healthy volunteers after oral administration of 60 mg naftopidil or placebo. Platelet aggregation in vitro was inhibited by naftopidil with a Ki value of 1.1 microM, the pIC50 was 5.09 with induction of aggregation by 1 microM 5-HT. After oral administration of naftopidil, 5-HT-induced aggregation was significantly inhibited by 36%. 4 h after naftopidil administration, 5-HT uptake velocity was reduced by 33%. Naftopidil not only cancelled the circadian increase in 5-HT-induced aggregation velocity observed during placebo application, but also caused a decrease in aggregation velocity directly after peak plasma naftopidil levels. 5-HT uptake in platelets was also reduced following peak naftopidil plasma concentrations. The 5-HT inhibitory action of naftopidil adds a third possible antihypertensive property to naftopidil's alpha 1-adrenoceptor blocking and Ca2+ antagonistic properties.

Dose-proportional plasma levels of the analgesic flupirtine maleate in man. Application of a new HPLC assay.

Single oral doses of the non-opioid, centrally-acting analgesic flupirtine maleate (Katadolon, CAS 75507-68-5) were administered to healthy volunteers and the 2 h plasma levels determined with a new specific HPLC assay. 50, 100, 200, and 300 mg were ingested as the commercial capsules in a double-blind randomized cross-over design with time intervals of at least 6 d. Dose-proportionality was observed for the median 2 h plasma levels which is in agreement with dose-proportionality previously described for multiple-dose studies.

Metabolic fate of the novel antihypertensive drug naftopidil.

The metabolism of 14C-naftopidil ((R,S)-1-(2-methoxyphenyl)-1-piperazinyl-3- (1-naphthyl-oxy-2-propanol, CAS 57149-07-2) and the pharmacodynamic action of the metabolites was investigated. The metabolic pathway in rat, dog, mouse and man was qualitatively similar, with preference for the hydroxylation of the phenyl or naphthyl moiety of naftopidil [phenyl)hydroxy-metabolite, (naphthyl)hydroxy-metabolite). Cleavage of the parent compound and production of the propylene glycol metabolite was a further important reaction especially for rat and man. In all species investigated, demethylation of naftopidil occurs to a minor extent. O-desmethyl-naftopidil, (phenyl)hydroxy-naftopidil and (naphthyl)hydroxy-naftopidil were found to have similar affinities for the alpha 1-adrenoceptors as the parent compound (IC50)nmol/l): 433.0; 585.0; 52.7; respectively; naftopidil: 235.0). The naftopidil metabolites, like the parent compound showed no alpha 2- or beta-adrenoceptor affinity.

Pharmacokinetic fate of the novel antihypertensive drug naftopidil.

The pharmacokinetics of naftopidil (R,S)-1-[4-(2-methoxyphenyl)-1-piperazinyl]-3-(1-naphthyloxy)-2 propanol, CAS 57149-07-2) was studied in rats and dogs using 14C-labeled drug in pharmacodynamically effective doses (oral doses: 5/10 mg/kg and intravenous doses: 1/2.5 mg/kg in rats/dogs, respectively). Naftopidil (14C) was rapidly and in high extent absorbed in rats and dogs after oral administration. The absolute bioavailability of the parent compound amounted to 9% in rats and indicates a high first pass effect to in part pharmacodynamically effective metabolites, as was shown in a previous paper. The parent compound and its 14C-metabolites were widely distributed into the periphery, more pronounced in the rat than in the dog, as indicated from comparison of the volumes of distribution and dose corrected Cmax- and AUC0-infinity-values in plasma. Elimination of radioactivity from plasma occurred in rat and dog in a similar rate. Tissue distribution studies in the rat showed highest peak-concentrations in the gastrointestinal (GI) tract (evaluated with contents) due to the predominant biliary elimination, followed by liver, adrenals, pituitary and Harderian glands, lungs, pancreas, kidneys, adipose tissue, bone marrow, aorta, thyroid and lymph nodes. Radioactivity was eliminated from most of the tissues within the first 168 h. Highest fractions of the dose were detected--apart from the GI-tract--in liver, muscle, skin, blood, and kidneys. After repeated administration to rats, accumulation of radioactivity in the 28 tissues examined did not exceed factor 9 or factor 5 in most of the tissues.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-related analgesic effects of flupirtine.

1. Flupirtine is a novel and, in all probability, centrally acting, analgesic. The present investigation was conducted in order to investigate dose-related effects of perorally administered flupirtine in man, with special regard to specifically analgesic actions, employing a model based on pain-related chemosomatosensory evoked potentials and subjective intensity estimates of painful stimuli. 2. Plasma concentrations of flupirtine measured 2 h after dosing linearly increased as a function of the administered dose. 3. It was possible to reproduce our own previously obtained results, which established the analgesic action of 200 mg flupirtine administered perorally. 4. Intensity estimates linearly decreased as a function of the administered dose, whereas chemosomatosensory evoked potential amplitudes non-linearly changed in relation to the administered dose. 5. In the spontaneous EEG, a dose-dependent increment in the power-spectra was observed, and this mainly in the alpha- and beta-range.

Kinetic evaluation of MAO-B-activity following oral administration of selegiline and desmethyl-selegiline in the rat.

The monoamine oxidase (MAO) B activity of rat brain was inhibited by selegiline and its desmethyl-metabolite in vitro with IC50-values of 11.25 nmol/l and 625.00 nmol/l, respectively. When measured in an ex vivo experiment following oral treatment of rats, the large difference in potency was distinctly reduced, from factor 60 in vitro to factor 3 ex vivo. Restoration experiments of MAO-B-activity after cessation of treatment revealed a nearly identical time course for both compounds. It is concluded that desmethyl-selegiline is an irreversible blocker of MAO-B, nearly equipotent to selegiline after multiple oral administration. No pharmacologically relevant inhibition of MAO-A was found with both compounds.

Pharmacokinetics of flupirtine in elderly volunteers and in patients with moderate renal impairment.

The pharmacokinetics of flupirtine after a single oral dose of 100mg have been studied in patients with moderate renal impairment and in healthy elderly subjects aged 66-83 years. Mean elimination half-life of flupirtine was higher in elderly patients than in younger normal subjects, and this was associated with an increased maximum serum concentration and reduced clearance. The mean half-life in patients with renal impairment was higher than in normal subjects. There was no correlation between observed elimination half-life and degree of renal impairment, but the creatinine clearance of most patients fell in a narrow range between 43 and 60 ml/min. In the light of these results and until further information is available, it would be prudent to start treatment of patients who are elderly or have evidence of renal impairment with half the dose of flupirtine recommended for younger patients with normal renal function.

Fenetylline: new results on pharmacology, metabolism and kinetics.

In the fenetylline molecule, theophylline is covalently linked with amphetamine via an alkyl chain. The inclusion of amphetamine and results from early metabolic studies have led to speculation that fenetylline may be merely a prodrug for amphetamine and/or theophylline. Although previous studies are not consistent with this hypothesis, additional studies were conducted to comparatively evaluate the profiles of activity exhibited by fenetylline and its two postulated primary metabolites, (+/-)-amphetamine and theophylline. Investigations were also initiated using newly developed high pressure liquid chromatography (HPLC) techniques to further characterize the metabolic pattern that fenetylline undergoes and to examine the relationship between plasma pharmacokinetics and the pharmacodynamic actions of the drug. Fenetylline inhibits activity associated with amphetamine in certain test systems, an effect similar to that previously observed with fenfluramine. Only small amounts of the amphetamine theoretically available in the fenetylline molecule are released. Pharmacodynamic activity associated with fenetylline administration is more closely tied to plasma levels of the parent compound than to any (+/-)-amphetamine produced.