II. Kinetics and metabolism of theobromine in male and female non-pregnant and pregnant rabbits

The kinetics and metabolism of theobromine (3,7-DMX) were investigated in male rabbits after a single oral dose and 14 days oral dosing at 1, 5, 10, 50 and 100 mg/kg/day. Female non-pregnant and pregnant rabbits were also studied after single oral doses of 1, 5 and 50 mg/kg. No significant difference was found in the pharmacokinetic profile of 3,7-DMX due to either sex, pregnancy or after chronic oral administration for 14 days. Intravenous (i.v.) administration of 3,7-DMX at 1 and 5 mg/kg resulted in calculated kinetic parameters in close agreement with oral doses. Irrespective of sex, there was a reduction in the absorption rate constant as the dose increased, coupled with a linear dose-related increase in AUC values. No qualitative difference in the metabolism of 3,7-DMX in the rabbit was observed as linked to sex, pregnancy or treatment schedule. Twenty-five percent of the administered dose of 3,7-DMX was excreted unchanged, the major metabolite being 7-methylxanthine (40%). There appeared to be a shift in the metabolic pathway at 100 mg/kg/day in the males and at 50 mg/kg/day in the females with more unchanged 3,7-DMX excreted. Only at these highest doses (100 mg/kg for males and 50 mg/kg for pregnant rabbits) was there a tendency toward accumulation.     

The pharmacokinetics of cimetidine and its sulphoxide metabolite in patients with normal and impaired renal function.

1 The pharmacokinetics of cimetidine and its sulphoxide metabolite was studied after a single intravenous dose of 200 mg cimetidine in nine patients with normal renal function and ten patients with severe renal failure on regular haemodialysis and during continuous oral cimetidine treatment in ten patients with normal renal function and 31 patients with different degrees of renal failure. 2 In normal renal function a mean of 47.3% of the single intravenous dose was excreted as unchanged drug and 12.8% as cimetidine sulphoxide. The mean plasma elimination half-life (T1/2) of cimetidine was 2.0 h and of cimetidine sulphoxide 1.7 h. 3 In severe renal failure a mean of 2.2% of the single intravenous dose was excreted as unchanged drug and 0.5% as cimetidine sulphoxide. The mean plasma T1/2 of cimetidine was 3.9 h. The plasma concentrations of the sulphoxide metabolite increased successively with time after dosing and no elimination phase was observed still 9 h after dose. The mean non-renal clearance of cimetidine was 210 ml/min and lower than in normal renal function, suggesting decreased metabolism of cimetidine in uraemia. 4 During continuous oral cimetidine treatment in patients with normal renal function and in patients g and no elimination phase was observed still 9 h after dose. The mean non-renal clearance of cimetidine was 210 ml/min and lower than in normal renal function, suggesting decreased metabolism of cimetidine in uraemia. 4 During continuous oral cimetidine treatment in patients with normal renal function and in patients g and no elimination phase was observed still 9 h after dose. The mean non-renal clearance of cimetidine was 210 ml/min and lower than in normal renal function, suggesting decreased metabolism of cimetidine in uraemia. 4 During continuous oral cimetidine treatment in patients with normal renal function and in patients with different degrees of renal failure given reduced doses of cimetidine the plasma concentrations of the sulphoxide metabolite were higher with decreasing renal function. The mean plasma T1/2 of cimetidine was 3.1 h in mild renal dysfunction (creatinine clearance 50-75 ml/min) and 4.5 h in severe renal failure (creatinine clearance 5-15 ml/min) and of cimetidine sulphoxide 5.3 and 14.4 h respectively. 5 Toxicity studies of cimetidine sulphoxide may be needed to assess if high plasma concentrations of the sulphoxide metabolite in severe renal failure are of clinical significance.     

Metabolism and disposition of clarithromycin in man

The metabolic fate and pharmacokinetics of clarithromycin following a single 250- or 1200-mg oral dose of 14C-clarithromycin were studied in six healthy adult males. Peak plasma levels of clarithromycin averaged 0.6 microgram/ml after the low dose and 2.7 micrograms/ml after the high dose. The AUC of clarithromycin increased 13-fold, with the 4.8-fold increase in dose, while the plasma half-life increased from 4.4 hr to 11.3 hr. The major metabolite in plasma and urine was the microbiologically active 14-hydroxylated-R epimer of clarithromycin. After 5 days, a mean of 38% of the low dose (18% as clarithromycin) and 46% of the high dose (29% as clarithromycin) was recovered in the urine, with approximately one-third eliminated during the first 24 hr. The nature of the urinary and fecal metabolites revealed the involvement of three metabolic pathways, viz. 1) hydroxylation at the 14-position to form the R and S epimers, 2) N-demethylation, and 3) hydrolysis of the cladinose sugar. Secondary metabolism via these pathways was also evident. The overall recovery of metabolites, but not total radioactivity, decreased 42% after the high dose. The nonlinear pharmacokinetic behavior of clarithromycin and the decrease in metabolite production suggest that clarithromycin metabolism can be saturated at high doses.     

In vivo and in vitro biotransformation of theobromine by phenobarbital- and 3-methylcholanthrene-inducible cytochrome P-450 monooxygenases in rat liver. Role of thiol compounds

A new in vitro method was developed and applied to establish the role of the hepatic cytochrome P-450 monooxygenases in theobromine biotransformation by control and phenobarbital (PB)- and 3-methylcholanthrene (3MC)-induced Sprague-Dawley rats. In vivo theobromine metabolite formation and pharmacokinetic parameters were also determined to serve as a comparison for in vitro studies. In vivo, the major urinary metabolite was 6-amino-5-[N-methylformylamino]-1-methyluracil (3,7DAU) with lesser amounts of 3,7-dimethyluric acid (3,7DMU), 3-methylxanthine, 7-methylxanthine, 7-methyluric acid, and traces of dimethylallantoin (DMA). Following induction with 3MC, but not PB, selective increases occurred in the urinary excretion of 3,7DAU, indicating that a 3MC-inducible cytochrome P-450 isozyme plays a significant role in this metabolic pathway. Both PB and 3MC induction increased slightly urinary elimination of DMA, a minor metabolite. Pharmacokinetic studies after a single oral dose of 5 mg/kg theobromine revealed a marked effect of 3MC treatment on theobromine elimination, as evidenced by a 59% decrease in theobromine t1/2, a 75% decrease in AUC, and a 284% increase in clearance. By contrast, PB had no effect. Fecal 14C elimination accounted for approximately 5% of the administered theobromine dose, and biliary excretion studies revealed the presence of 3,7DMU, DMA, 3,7DAU, and unchanged theobromine. Studies in vitro indicated that 3,7DMU was the major theobromine metabolite produced by liver microsomes. Conversion rates in PB- and 3MC-induced rats were 2- and 11-fold higher, respectively, than in controls.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disposition of acrivastine in the male beagle dog.

Three male beagle dogs were given 10 mg/kg iv and oral doses of [14C]acrivastine, a novel nonsedating antihistaminic agent, in a nonrandomized crossover experiment. Urine and feces were collected for 72 hr after dosing. After iv dosing, a mean of 34% was recovered in the urine, and 63% was recovered in the feces. After po dosing, a mean of 29% of the radiocarbon was recovered in the urine, and 63% was recovered in the feces (dose adjusted for 14% lost in vomitus). Acrivastine and three major metabolites were detected in the excreta. The metabolites were identified as a side-chain-reduced analog of acrivastine (metabolite 3, 270C81), a gamma-aminobutyric acid analog of 270C81 (metabolite 2), and a benzoic acid analog of 270C81 (metabolite 1). After iv dosing, 34% of the dose was excreted as parent drug, 21% as metabolite 3, 15% as metabolite 2, and 6% as metabolite 1, while after po dosing, 35% of the dose was excreted as parent drug, 18% as metabolite 3, 11% as metabolite 2, and 7% as metabolite 1. Pharmacokinetic analysis of acrivastine plasma concentration-time curves after both routes of administration indicated a mean total body clearance of 17.3 ml/min/kg, a Vss of 0.93 liter/kg, a terminal half-life of 0.7 hr, and an oral bioavailability of 40%. The apparent plasma half-life of the metabolite, 270C81, was 1.5 hr. Analysis of AUC values indicated that greater amounts of 270C81 than acrivastine circulated in plasma after both iv and po dosing, and that first-pass metabolism of acrivastine to 270C81 occurred. The results indicated that acrivastine was extensively metabolized in the dog to 270C81 and suggested that 270C81 itself underwent further metabolism to metabolites 1 and 2.     

Excretion and metabolism of milnacipran in humans after oral administration of milnacipran hydrochloride

The pharmacokinetics, excretion, and metabolism of milnacipran were evaluated after oral administration of a 100-mg dose of [(14)C]milnacipran hydrochloride to healthy male subjects. The peak plasma concentration of unchanged milnacipran (～240 ng/ml) was attained at 3.5 h and was lower than the peak plasma concentration of radioactivity (～679 ng Eq of milnacipran/ml) observed at 4.3 h, indicating substantial metabolism of milnacipran upon oral administration. Milnacipran has two chiral centers and is a racemic mixture of cis isomers: d-milnacipran (1S, 2R) and l-milnacipran (1R, 2S). After oral administration, the radioactivity of almost the entire dose was excreted rapidly in urine (approximately 93% of the dose). Approximately 55% of the dose was excreted in urine as unchanged milnacipran, which contained a slightly higher proportion of d-milnacipran (～31% of the dose). In addition to the excretion of milnacipran carbamoyl O-glucuronide metabolite in urine (～19% of the dose), predominantly as the l-milnacipran carbamoyl O-glucuronide metabolite (～17% of the dose), approximately 8% of the dose was excreted in urine as the N-desethyl milnacipran metabolite. No additional metabolites of significant quantity were excreted in urine. Similar plasma concentrations of milnacipran and the l-milnacipran carbamoyl O-glucuronide metabolite were observed after dosing, and the maximum plasma concentration of l-milnacipran carbamoyl O-glucuronide metabolite at 4 h after dosing was 234 ng Eq of milnacipran/ml. Lower plasma concentrations (<25 ng Eq of milnacipran/ml) of N-desethyl milnacipran and d-milnacipran carbamoyl O-glucuronide metabolites were observed.     

Effect of diet and gavage on the dose- and dose-mode-dependent absorption and metabolism of bidisomide in rat

1. The metabolism of bidisomide was investigated to examine how dose and mode of drug administration (i.e. diet admixture versus oral solution) affect the absorption and metabolism of bidisomide in the toxicity studies. 2. After dietary admixture, bidisomide was more absorbed and less metabolized at the higher doses. Reduced metabolism at the high doses resulted from saturation of stereospecific formation of the N-desisopropyl-arylhydroxy bidisomide (NDABD) metabolite. 3. The rat-specific NDABD metabolite was formed only from (-)-bidisomide on incubation with rat liver microsomes. 4. After oral solution dosing, absorption was increased and metabolism reduced compared with the dietary admixture. 5. After 24-h infusion, plasma concentrations of radioactivity were approximately dose-proportional. However, the concentrations in the liver were similar at the 200 and 400?mg/kg doses due to saturation of liver uptake of the NDABD metabolite.     

Effect of toluidines and dinitrotoluenes on caffeine metabolic ratio in rat

Caffeine (1,3,7-trimethylxanthine, CA) is metabolised by N-demethylation to three primary metabolites: theophylline (TP), paraxanthine (PX) and theobromine (TB). This process is mediated in 95% by CYP1A2. Thus the measurement of CA demethylated metabolites can be used as a marker of CYP1A2 activity in vivo. In the present study, caffeine and its primary metabolites were determined simultaneously in plasma of rats pretreated with three isomers of toluidine at doses: 1, 10, 60 mg/kg b.w., p.o. and four isomers of dinitrotoluene (DNT) at doses: 100 and 200 mg/kg b.w., p.o. Caffeine metabolite ratios in plasma: TB/CA, PX/CA, TP/CA, TB + PX + TP/CA were calculated and compared to those of control rats. Administration of toluidines resulted in a 2-20 fold increase of the concentration ratios of metabolites to caffeine. All toluidines seem to be inducers of CYP1A2. To the best of our knowledge this is the first information concerning the effect of toluidines on caffeine metabolism. Two out of the four tested dinitrotoluenes slightly affected CYP1A2 activity; 2,3- and 3,4-DNT increased estimated parameters 2-6 fold. Two others, 2,4- and 2,6-DNT can be considered as moderate hepatotoxic agents decreasing CA metabolic ratios to 4-70% of the control values.     

Pharmacokinetic characteristics of bornaprolol in healthy volunteers

1. Six young male volunteers received five single doses of bornaprolol, i.v. (20 mg) and orally (120, 240, 480, 960 mg) administered at 2-week intervals. Plasma concentrations of bornaprolol and its conjugated metabolite were determined by gas chromatography. 2. After i.v. administration, plasma bornaprolol levels were detectable over 8 h, and mean values were 60 l/h for total clearance (C1), 207 l for volume of distribution (V beta), 2.6 h for elimination half-life (t1/2 beta). After oral administration, plasma bornaprolol levels were detectable over 24-48 h, and mean values of pharmacokinetics parameters were 60 l/h for C1, 1500 l for V beta, 20 h for t1/2 beta. Maximum plasma concentrations and area under the plasma concentration-time curve increased in a non-dose-dependent manner. 3. The glucuronide conjugate appeared in the blood within 5-10 min and its plasma level greatly exceeded bornaprolol concentrations. The mean value of the ratio of the metabolite AUC/parent product AUC was 14 after i.v. administration and 13-21 following oral administration, depending on dose. The AUC for the metabolite did not increase proportionally with oral doses. 4. Bornaprolol is principally eliminated after metabolism. This process did not increase with increasing oral doses and bioavailability seemed to decrease inversely with oral dose.     

Amiodarone pharmacokinetics in coronary patients: differences between acute and one-month chronic dosing

The pharmacokinetics of amiodarone (A) and its desethylamiodarone metabolite (DEA) were compared in the same coronary patients after a first 1000 mg dose and one-month chronic oral dosing. Terminal half-life (t1/2 el) of amiodarone increased from a mean (SD) 24.1 +/- 19.5 h after the first dose to 20.4 +/- 4.8 days after the last dose. Desethylamiodarone slowly appeared in the plasma after the first oral dose and its apparent t el was 61.6 +/- 26.6 h. After one-month dosing apparent t1/2 el of desethylamiodarone increased to 29.5 +/- 9.7 days. Mean maximal plasma amiodarone/desethylamiodarone concentration ratio decreased from 9.2 +/- 5.0 to 2.0 +/- 0.6 after chronic dosing. This change was mainly related to an increase in the plasma concentration of desethylamiodarone. These data suggest that after long-term treatment with amiodarone, the complete elimination of the drug and its metabolite may need 3-4 months in some patients. The results of this study were presented in part at the meeting of the Societe Francaise de Therapeutique et de Pharmacologie Clinique, Paris, December 1985.     

Inhibitory and inducing effects of denzimol on carbamazepine metabolism in the rat

In vivo and in vitro alterations in carbamazepine (CBZ) metabolism and the extent of enzyme induction of the hepatic cytochrome P-450 system after chronic oral denzimol to rats were evaluated. No effect on drug-metabolizing enzymes was detected for this new anticonvulsant drug at a dose of 15 mg/kg, which is just above the anticonvulsive dose. At higher doses (60 mg/kg) denzimol significantly raised the hepatic cytochrome P-450 content, enhanced CBZ clearance and tend to shorten its elimination t1/2 and that of its active metabolite. These results, combined with those of a previous study showing impairment of CBZ metabolism after single doses of denzimol, suggest that the drug may have either inductive or inhibitory effects on microsomal mixed-function oxidase activity in the rat, depending on the dose and schedule of treatment.     

Effect of diet and gavage on the dose- and dose-mode-dependent absorption and metabolism of bidisomide in rat

1. The metabolism of bidisomide was investigated to examine how dose and mode of drug administration (i.e. diet admixture versus oral solution) affect the absorption and metabolism of bidisomide in the toxicity studies. 2. After dietary admixture, bidisomide was more absorbed and less metabolized at the higher doses. Reduced metabolism at the high doses resulted from saturation of stereo-specific formation of the N-desisopropyl-arylhydroxy bidisomide (NDABD) metabolite. 3. The rat-specific NDABD metabolite was formed only from (-)-bidisomide on incubation with rat liver microsomes. 4. After oral solution dosing, absorption was increased and metabolism reduced compared with the dietary admixture. 5. After 24-h infusion, plasma concentrations of radioactivity were approximately dose-proportional. However, the concentrations in the liver were similar at the 200 and 400 mg/kg doses due to saturation of liver uptake of the NDABD metabolite.     

Dose independent pharmacokinetics of caffeine after intravenous administration under a chronic food-limited regimen

Several studies have shown that caffeine follows non-linear pharmacokinetics in both rats and humans. Recent data have demonstrated that caffeine may following linear pharmacokinetics when administered orally and intraperitoneally to food-limited rats. In this study the pharmacokinetics of caffeine was analyzed following intravenous (i.v.) administration to rats under a food-limited regimen. Four rats were administered four doses of caffeine and a standard dose of the caffeine metabolites, paraxanthine, theobromine, and theophylline. Caffeine pharmacokinetic parameters were dose independent following intravenous doses ranging from 1 to 20 mg/kg. Furthermore, the caffeine area under the curve (AUC) increased linearly as a function of dose. The mean fraction of caffeine converted to paraxanthine, theobromine, and theophylline was 16%, 16%, and 7%, respectively. The linear pharmacokinetics demonstrated in the present study may be attributed to the induction of hepatic metabolism under a chronic food-limited regimen.     

Studies on benzyl acetate. I. Effect of dose size and vehicle on the plasma pharmacokinetics and metabolism of [methylene-14C]benzyl acetate in the rat

Male Fischer 344 rats received [methylene-¹⁴C]benzyl acetate by gavage in a dose of 5, 250 or 500 mg/kg, as the neat substance, in corn oil or in propylene glycol. Urine and faeces were collected and urinary metabolites were assayed by radio-TLC and HPLC. Other animals were killed at various times and exsanguinated, and plasma levels of ¹⁴C in plasma occurred earliest and were highest when benzyl acetate was given neat. Peak levels were lower and absorption was delayed with the propylene glycol vehicle. The use of corn oil as the dose vehicle at the higher doses (250 and 500 mg/kg) led to the maintenance of plateau plasma levels, at about one half of the peak levels seen with the neat compound, for up to 8 hr after administration. At the 5 mg/kg dose, the plasma levels of ¹⁴C were essentially the same whether the dose was given in corn oil or propylene glycol. At the 250- and 500-mg/kg doses, at all time points, the major metabolite in plasma was benzoic acid, accompanied by smaller amounts of hippuric acid. Benzyl alcohol was also detected in some plasma samples. At the 5-mg/kg dose, the major plasma metabolite was hippuric acid, together with a smaller amount of benzoic acid. When propylene glycol was used as the vehicle at this dose level, benzylmercapturic acid was also present in the plasma. The major urinary metabolite was hippuric acid (c. 66% of the dose), with benzoic acid (2%) and benzylmercapturic acid (1%) also present. The elimination of benzoyl glucuronide increased with increasing dose, from c. 3 to 11% of the dose.     

Low-dose fluvoxamine as an adjunct to reduce olanzapine therapeutic dose requirements: a prospective dose-adjusted drug interaction strategy

Despite the advances in antipsychotic pharmacotherapy over the past decade, many atypical antipsychotic agents are not readily accessible by patients with major psychosis or in developing countries where the acquisition costs may be prohibitive. Olanzapine is an efficacious and widely prescribed atypical antipsychotic agent. In theory, olanzapine therapeutic dose requirement may be reduced during concurrent treatment with inhibitors of drug metabolism. In vitro studies suggest that smoking-inducible cytochrome P450 (CYP) 1A2 contributes to formation of the metabolite 4'-N-desmethylolanzapine. The present prospective study tested the hypothesis that olanzapine steady-state doses can be significantly decreased by coadministration of a low subclinical dose of fluvoxamine, a potent inhibitor of cytochrome P450 1A2. The study design followed a targeted "at-risk" population approach with a focus on smokers who were likely to exhibit increased cytochrome P450 1A2 expression. Patients with stable psychotic illness (N = 10 men, all smokers) and receiving chronic olanzapine treatment were evaluated for steady-state plasma concentrations of olanzapine and 4'-N-desmethylolanzapine. Subsequently, olanzapine dose was reduced from 17.5 +/- 4.2 mg/d (mean +/- SD) to 13.0 +/- 3.3 mg/d, and a nontherapeutic dose of fluvoxamine (25 mg/d, PO) was added to regimen. Patients were reevaluated at 2, 4, and 6 weeks during olanzapine-fluvoxamine cotreatment. There was no significant change in olanzapine plasma concentration, antipsychotic response, or metabolic indices (eg, serum glucose and lipids) after dose reduction in the presence of fluvoxamine (P > 0.05). 4'-N-desmethylolanzapine/olanzapine metabolic ratio decreased from 0.45 +/- 0.20 at baseline to 0.25 +/- 0.11 at week 6, suggesting inhibition of the cytochrome P450 1A2-mediated olanzapine 4'-N-demethylation by fluvoxamine (P < 0.05). In conclusion, this prospective pilot study suggests that a 26% reduction in olanzapine therapeutic dose requirement may be achieved by coadministration of a nontherapeutic oral dose of fluvoxamine.     

Toxicokinetics and metabolism of N-[14C]methylpyrrolidone in male Sprague-Dawley rats. A saturable NMP elimination process.

This study evaluated the toxicokinetics of N-[(14)C]methylpyrrolidone ([(14)C]NMP) after intravenous administration (0.1, 1, 10, 100, and 500 mg/kg, in saline solution) or topical application (20 and 40 micro l/cm(2); 10 cm(2), neat) in haired male Sprague-Dawley rats. Whatever the dose, unchanged NMP was intensively distributed into the body with a volume of distribution of 69% of body weight. After this phase, unchanged NMP declined almost linearly with time for 3 to 4 h after administration and then followed a mono-exponential function (t1/2 = 0.8 h) for the three lowest doses. The maximal plasma level of 5-hydroxy-N-methylpyrrolidone (5-HNMP), the main metabolite, was reached 4 to 6 h later for the three lowest doses and 8 to 24 h later for the highest doses. These findings indicate that the elimination of NMP is governed by a saturable metabolism process. The Michaelis-Menten parameters estimated from plasma levels of unchanged NMP were 2 mM and 3.8 mg/h, respectively. Between 4 and 10% of the administered doses were excreted in the urine as unchanged NMP. Urinary clearance of NMP (0.03 to 0.07 ml/min) indicates intensive tubular reabsorption. 5-HNMP was the main urinary metabolite and accounted for 42 to 55% of the administered doses. Its maximal urinary excretion occurred between 4 and 6 h after administration of the three lowest doses and between 8 and 24 h for the two highest doses. Urinary clearance (0.9 to 1.3 ml/min) was compatible with renal elimination by simple glomerular filtration.     

Influence of dose and route of administration on the kinetics of fluoxetine and its metabolite norfluoxetine in the rat

Fluoxetine (FL) is being used in neuropharmacology as a tool for studying various functional roles of serotoninergic neurons. Its kinetics was studied in rats, a species widely used in neurochemical studies, after IV (2.5–10 mg/kg) and oral (5–20 mg/kg) administration. When injected IV the drug followed apparent first-order kinetics up the 10 mg/kg dose. Its volume of distribution was large and total body clearance was relatively high compared to liver blood flow. The mean elimination half-lives (t _1/2) of FL and its active metabolite norfluoxetine (NFL) were about 5 and 15 h, respectively. The mean blood:plasma concentration ratios of FL and NFL approached unity and plasma protein binding was 85–90% for both compounds. After oral doses the kinetics of FL were complex. At the lowest dose tested (5 mg/kg) the drug was efficiently extracted by the liver (extraction ratio about 60%), resulting in bioavailability of only about 38%. Plasma areas under the curve (AUC) of the metabolite were approximately the same as after IV injection of the same dose; consequently the metabolite-to-parent drug ratio after oral administration (about 5) was approximately twice that after IV injection of FL (about 2.5). At higher doses, however, the oral bioavailability (e.g.C _max and AUC) appeared greater than expected, possibly because of transient saturation of FL first-pass metabolism in the case of the 10 mg/kg dose and concomitant saturation of elimination kinetics at the higher dose (20 mg/kg). The apparent eliminationt _1/2 of FL markedly increased and the metabolite-to-parent drug ratio declined with the higher dose, this also being consistent with saturable elimination. Brain concentrations reflected the plasma kinetics of FL and NFL and the metabolite-to-parent drug ratio varied with dose and time of administration and was modified at the highest dose tested. FL and its metabolite NFL distributed almost evenly in discrete brain areas and subcellular distribution was similar for both compounds. Neurochemical studies of FL should consider the formation of the active metabolite NFL and extrapolation of data across animal species requires consideration of dose dependence in the rat.     

Pharmacokinetic parameters of tibolone and metabolites in plasma, urine, feces, and bile from ovariectomized cynomolgus monkeys after a single dose or multiple doses of tibolone.

Levels of nonsulfated and sulfated tibolone metabolites were determined in plasma, urine, and feces from six ovariectomized, mature female cynomolgus monkeys after a single dose and multiple p.o. doses (including bile) of tibolone using validated gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry assays. In plasma, the predominant nonsulfated metabolite after single and multiple dosing was the estrogenic 3alpha-hydroxytibolone; levels of the estrogenic 3beta-hydroxytibolone were 10-fold lower and of progestagenic/androgenic Delta(4)-tibolone, 5-fold lower. Tibolone was undetectable. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone; levels of 3betaS,17betaS-tibolone were about 2-fold lower, and monosulfated 3-hydroxymetabolites were about 10-fold lower. After multiple doses, areas under the curve of nonsulfated metabolites were lower (2-fold), and those of sulfated metabolites were 25% higher. In plasma, >95% metabolites were disulfated. In urine, levels of all the metabolites after single and multiple doses were low. After a single dose, high levels of 3beta-hydroxytibolone and the 3-monosulfated metabolites (3betaS,17betaOH-tibolone and 3alphaS,17betaOH-tibolone) were found in feces. After multiple dosing, 3alpha-hydroxytibolone increased, and the ratio of 3alpha/3beta-hydroxytibolone became about 1. The predominant sulfated metabolite was 3alphaS,17betaS-tibolone. Levels of all the metabolites in feces were higher after multiple doses than after a single dose. Levels of nonsulfated and 3-monosulfated metabolites were higher in feces than in plasma. Bile contained very high metabolite levels, except monosulfates. This may contribute to the metabolite content of the feces after multiple doses. 3beta-Hydroxytibolone and 3alphaS,17betaS-tibolone predominated. In conclusion, tibolone had different metabolite patterns in plasma, urine, feces, and bile in monkeys. The bile contributed to the metabolite pattern in feces after multiple doses. The major excretion route was in feces.     

Pharmacokinetics of chlorambucil in patients with chronic lymphocytic leukaemia: comparison of different days, cycles and doses

The effects of repeated treatment cycles and different doses on intraindividual variation in oral bioavailability of chlorambucil and its first, active, and more toxic metabolite, phenylacetic acid mustard, were studied. Chlorambucil and phenylacetic acid mustard concentrations were measured with HPLC on Day 1 and on Day 4 in 15 timed blood samples from 11 chronic lymphocytic leukaemia patients receiving chlorambucil therapy cycles. Bioavailability was evaluated also after the first chlorambucil doses of six consecutive treatment cycles repeated every 4 weeks with increasing chlorambucil doses starting with 0.8 mg/kg/4 days, and increased by 0.1 mg/kg/4 days cycle. Area under the concentration-time-curve (AUC) from t=0 to infinite was in average 3.2 hr* microg/ml for the first cycle, and decreased by 17% in four days (P<0.05). The mean distribution half-life of chlorambucil was 0.49 hr and the terminal elimination half-life 2.45 hr. The bioavailability of chlorambucil decreased further when 4-day treatment cycles were repeated. For the fifth cycle, dose-corrected AUC for the first 2 hr was 33% smaller than that for the first cycle (P for trend <0.01). Data suggest accelerated metabolism and elimination of chlorambucil and phenylacetic acid mustard, but reduced oral bioavailability of chlorambucil cannot be excluded. However, except for AUC, none of the pharmacokinetic parameters of chlorambucil changed significantly during the first 4-day treatment period. The maximal plasma concentration and AUC of phenylacetic acid mustard did not change significantly during repeated treatment cycles. According to this trial a dose adjustment of chlorambucil is not necessary during a short-term course, but may be necessary when treatment cycles are repeated. An average increase in the chlorambucil dose of 10% per cycle maintains similar plasma concentration of chlorambucil.     

Interspecies and interstrain studies on the increased susceptibility to metrazol-induced convulsions in animals given aspartame

The ability of aspartame (APM) to increase the susceptibility to metrazol-induced convulsions was studied in two strains of mice (CD1 and DBA/2J) and in guinea-pigs. Rats were included as known positive controls. Plasma and brain levels of phenylalanine (Phe) and tyrosine (Tyr) were measured in CD1 mice and guinea-pigs at various intervals after a dose of 1 g APM/kg body weight (administered orally to mice and ip to guinea-pigs). In mice, peak levels of Phe and Tyr were observed in plasma after 30 min and in brain after 60 min. In guinea-pigs peak plasma levels of Phe and Tyr occurred 30 min after treatment. Phe was at a maximum in guinea-pig brain after 30 min, while Tyr levels reached a peak at 120 min. In further experiments Phe and Tyr levels were measured 1 hr after APM doses of 0.5, 0.75 or 1 g/kg. In CD1 mice, plasma Phe and Tyr levels were increased significantly only at the highest dose, whereas in brain, Tyr concentrations were significantly increased by 0.75 or 1 g APM/kg and Phe was significantly increased by all three doses. In the guinea-pig, plasma Phe and Tyr were increased significantly only by 1 g APM/kg and in brain this dose significantly raised only the Phe levels. Monoamine and metabolite levels were determined in the brain striata of CD1 and DBA/2J mice 1 hr after the oral administration of 1 or 2 g APM/kg body weight; no differences from control values were found in either strain. The studies of potentiation of metrazol-induced convulsions showed that APM, at doses of up to 2 g/kg body weight, had no such effect in mice or guinea-pigs. In contrast, as expected, the potentiation was significant in the rat at 1 g/kg.