A pharmacokinetic model to predict the PK interaction of L-dopa and benserazide in rats.

PURPOSE: To study the PK interaction of L-dopa/benserazide in rats. METHODS: Male rats received a single oral dose of 80 mg/kg L-dopa or 20 mg/kg benserazide or 80/20 mg/kg L-dopa/benserazide. Based on plasma concentrations the kinetics of L-dopa, 3-O-methyldopa (3-OMD), benserazide, and its metabolite Ro 04-5127 were characterized by noncompartmental analysis and a compartmental model where total L-dopa clearance was the sum of the clearances mediated by amino-acid-decarboxylase (AADC), catechol-O-methyltransferase and other enzymes. In the model Ro 04-5127 inhibited competitively the L-dopa clearance by AADC. RESULTS: The coadministration of L-dopa/benserazide resulted in a major increase in systemic exposure to L-dopa and 3-OMD and a decrease in L-dopa clearance. The compartmental model allowed an adequate description of the observed L-dopa and 3-OMD concentrations in the absence and presence of benserazide. It had an advantage over noncompartmental analysis because it could describe the temporal change of inhibition and recovery of AADC. CONCLUSIONS: Our study is the first investigation where the kinetics of benserazide and Ro 04-5127 have been described by a compartmental model. The L-dopa/benserazide model allowed a mechanism-based view of the L-dopa/benserazide interaction and supports the hypothesis that Ro 04-5127 is the primary active metabolite of benserazide.

Single- and multiple-dose pharmacokinetics, kidney tolerability and plasma protein binding of tenoxicam in renally impaired patients and healthy volunteers.

The 20 mg single-dose and 12 days repeated-dose pharmacokinetics of tenoxicam and the 5-OH-tenoxicam metabolite have been evaluated in healthy volunteers and two groups of patients with different degree of renal impairment, in total 20 persons. Concomitantly, the plasma protein binding of tenoxicam and the effects of treatment on renal function were evaluated. No differences were found between the investigated groups in the pharmacokinetics of total tenoxicam and the 5-OH metabolite did not interfere either with the pharmacokinetics or with the plasma protein binding of tenoxicam. A positive correlation was found between an increase in the free fraction (% F) of tenoxicam in plasma and a decrease in the plasma elimination half-life in the low creatinine clearance group (40-20 ml/min.) both after the single-dose and at steady-state. At steady-state, a non-linear correlation was demonstrated between a decrease in the urinary excretion of the 5-OH metabolite and a decrease in creatinine clearance from 130 to 20 ml/min. An increase in the plasma level of the 5-OH metabolite by three times was found in the low creatinine clearance group as compared to healthy subjects. 14C-Impurities of tenoxicam, as low as 1.2%, were shown to greatly influence the determination of the plasma protein binding (equilibrium dialysis) of the highly protein-bound tenoxicam due to a non-binding ability of the impurities to plasma proteins. No significant changes in renal parameters were found during the study. It can be concluded that the pharmacokinetics and plasma protein binding of tenoxicam and the pharmacokinetics of the 5-OH-tenoxicam metabolite are increasingly changed in subjects with a creatinine clearance below 40 ml/min. A decreased binding of tenoxicam to plasma proteins in low clearance patients is probably the reason for a faster elimination of tenoxicam in this group rather than a higher intrinsic hepatic metabolic activity. This study conducted in a low number of patients did not bring forward any new data indicating any adverse effects of tenoxicam on renal function.

Plasma levels of the enantiomers of thioridazine, thioridazine 2-sulfoxide, thioridazine 2-sulfone, and thioridazine 5-sulfoxide in poor and extensive metabolizers of dextromethorphan and mephenytoin.

Concentrations of total (R) + (S) and of the enantiomers (R) and (S) of thioridazine and metabolites were measured in 21 patients who were receiving 100 mg thioridazine for 14 days and who were comedicated with moclobemide (450 mg/day). Two patients were poor metabolizers of dextromethorphan and one was a poor metabolizer of mephenytoin. Cytochrome P450IID6 (CYP2D6) is involved in the formation of thioridazine 2-sulfoxide (2-SO) from thioridazine and also probably partially in the formation of thioridazine 5-sulfoxide (5-SO), but not in the formation of thioridazine 2-sulfone (2-SO2) from thioridazine 2-SO. Significant correlations between the mephenytoin enantiomeric ratio and concentrations of thioridazine and metabolites suggest that cytochrome P450IIC19 could contribute to the biotransformation of thioridazine into yet-unknown metabolites, other than thioridazine 2-SO, thioridazine 2-SO2, or thioridazine 5-SO. An enantioselectivity and a large interindividual variability in the metabolism of thioridazine have been shown: measured (R)/(S) ratios of thioridazine, thioridazine 2-SO fast eluting (FE), thioridazine 2-SO slow eluting (SE), thioridazine 2-SO (FE+SE), thioridazine 2-SO2, thioridazine 5-SO(FE), and thioridazine 5-SO(SE) were (mean +/- SD) 3.48 +/- 0 .93 (range, 2.30 to 5.80), 0.45 +/- 0.22 (range, 0.21 to 1.20), 2.27 +/- 8.1 (range, 6.1 to 40.1), 4.64 +/- 0.68 (range, 2.85 to 5.70), 3.26 +/- 0.58 (range, 2.30 to 4.30), 0.049 +/- 0.019 (range, (0.021 to 0.087), and 67.2 +/- 66.2 (range, 16.8 to 248), respectively. CYP2D6 is apparently involved in the formation of (S)-thioridazine 2-SO(FE), (R)-thioridazine 2-SO(SE), and also probably (S)-thioridazine 5-SO(FE) and (R)-thioridazine 5-SO(SE).

Antidepressants and drug-metabolizing enzymes--expert group report.

Antidepressant drugs are extensively metabolized. Consequently, the biotransformation pattern of antidepressants has an important influence on their clinical properties, i.e., pharmacokinetics, toxicity, drug-drug interactions, side-effect profile and last but not least therapeutic efficacy. It was against this background that a multidisciplinary group of experts discussed the clinical relevance of the rapidly increasing body of knowledge of antidepressant-metabolizing enzymes. The variability of the response of a given individual to an antidepressant is determined genetically and by the environment. Genetic polymorphism of drug-metabolizing enzymes and inhibition by other substrates may affect the enzymatic biotransformation of antidepressants. In vitro assay techniques allow an estimation of the potential variability in clinical response to antidepressants and a reasonable prediction of the drug-drug interaction patterns. The results of in vitro tests should therefore be considered early in the development of an antidepressant as a background for designing clinical studies (treatment schedules and dosing). Physicians should have an understanding of the relevance of genetic polymorphism for clinical practice. Education is needed in order to fill the existing gaps in knowledge about antidepressant-enzyme interactions and their application in daily treatment practice. The information on potential drug interactions determined by genetic polymorphism and based on studies with enzymes should be increasingly contained in drug compendia.

Clinical pharmacokinetics of the monoamine oxidase-A inhibitor moclobemide.

There has been a resurgence of interest in the use of monoamine oxidase (MAO) enzyme inhibitors for the treatment of depression. Unlike the first-generation MAO inhibitors, the current drugs are readily reversible in their action, resulting in far less concern about interactions with certain foods and drugs which could lead to serious pressor effects. Furthermore, the current drugs are far more selective in their actions as a result of the ability to affect either the MAO-A or the MAO-B isoenzyme. Moclobemide is an example of a reversible MAO-A inhibitor which has been extensively studied and whose pharmacokinetic, clinical pharmacological and toxicological profiles have been thoroughly defined. Moclobemide has a short disposition half-life and intermediate values for systemic clearance and volume of distribution; half-life increases somewhat with dose. The drug is completely metabolised by the liver. Moclobemide is rapidly and completely absorbed following oral administration in a variety of dosages and forms. The drug has a high intrinsic (apparent oral) clearance which results in a substantial hepatic first-pass effect and, while there is marked interindividual variation, differences within an individual are small. A time- and dose-dependence is observed with multiple oral administration: clearance decreases with administration during the first week and thereafter remains constant. The exact mechanism of this effect is not known, but it may reflect inhibition of elimination by metabolites (the kinetics may always be described as being first-order). Moclobemide disposition is not affected by renal disease, nor is there substantial alteration with advanced age. Liver disease causes a dramatic reduction in clearance; dosage must be adjusted for patients with liver disease. There is minimal transfer of the drug into breast milk, such that breast-feeding neonates are exposed to only a very small dose of the drug. Moclobemide administration results in a minimal interaction with exogenous amines (e.g. tyramine and pressor amine drugs); the so-called 'cheese effect' is therefore of little concern. As a result, the drug has an excellent tolerability profile both within the therapeutic dose range and in overdose (no deaths have been attributed to moclobemide intoxication per se). Cimetidine inhibits the elimination of moclobemide. Moclobemide appears to affect several isoenzymes of the cytochrome P450 (CYP) system (CYP2C19, CYP2D6 and CYP1A2). The adverse events profile of moclobemide indicates only mild and transient effects at a relatively low rate of occurrence.

Moclobemide: relationships between dose, drug concentration in plasma, and occurrence of adverse events.

The relationship between exposure to moclobemide and the occurrence of adverse events (AEs) was quantified by applying a population approach to data collected during phase III/IV studies. A total of 965 measurements of moclobemide concentration in plasma were available from 357 depressed patients included in a series of clinical studies; 539 AEs were reported by the 236 patients with at least one concentration measurement > or = 400 micrograms/liter. Using relatively few blood samples per patient (mean, 2.7), the average concentration in plasma on the day an AE was observed was calculated (CAE,pred) from population kinetic parameter estimates. The frequency of AEs, normalized by exposure time in months (AEs/Mo), was grouped according to dose and concentration categories and examined in relation to age, gender, adverse event severity, and concomitant medication. CAE,pred was more powerful than the observed concentration or daily dose in detecting relationships between exposure to moclobemide and the occurrence of AEs. There was a relationship between CAE,pred and AEs/Mo, with 0.58 events at concentrations between 1,000 and 1,999 micrograms/liter and 2.78 events at concentrations of 4,000 micrograms/liter and above. Within each concentration category, the number of AEs decreased with increasing severity. Advancing age was not associated with an increase of AEs/Mo. AEs were more frequent in females than in males in all treatment intensity categories (ratio, 1.4). There was no indication of supra-additive effects by concomitant medication, including all drugs used in the study population. This investigation demonstrates the successful use of observational data from clinical studies in the assessment of quantitative relationships between drug exposure and the occurrence of AEs.

Moclobemide, a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6, and CYP1A2: a panel study.

The reversible monoamine oxidase A inhibitor moclobemide was given in single (300 mg) and multiple doses (600 mg/day) to 11 male and four female healthy volunteers (age range, 23 to 27) who were either poor metabolizers of S-mephenytoin (n = 7) or extensive metabolizers of S-mephenytoin (n = 8). All were extensive metabolizers of sparteine. Poor metabolizers of S-mephenytoin had lower moclobemide clearance values (median, single dose: 16.1 versus 43.2 L.hr-1; steady state: 13.4 versus 22.1 L.hr-1) and longer moclobemide half-life values (median, single dose: 4.0 versus 1.8 hours; steady state: 5.1 versus 2.7 hours) than extensive metabolizers of S-mephenytoin. The plasma levels of a metabolite formed by C-hydroxylation (Ro 12-8095) were lower in poor metabolizers of S-mephenytoin than in extensive metabolizers of S-mephenytoin. Moclobemide thus partially undergoes oxidative metabolism by way of the polymorphic CYP2C19. A combined mephenytoin, sparteine, and caffeine test performed before, during, and after multiple dosing of moclobemide showed changes in the metabolic indexes compatible with a reversible inhibition of oxidation by way of the corresponding CYP enzymes--CYP2C19, CYP2D6, and CYP1A2--during moclobemide treatment.

Relative bioavailability of oral dosage forms of tenoxicam.

The bioavailability of tenoxicam (Ro 12-0068, Tilcotil, CAS 59804-37-4) from an effervescent tablet and an instant milk drink formulation relative to the commercial 20 mg tablet was investigated in a randomized cross-over study. Twelve healthy male volunteers (age 18-35 years; weight 63-95 kg) received on three different occasions a single oral tablet, an effervescent tablet or an instant milk drink (dissolved in water) with each dose containing 20 mg of tenoxicam. The wash-out period between two consecutive treatments was at least 5 weeks. Plasma concentrations after dosing were determined with a specific HPLC method. With the effervescent tablet and the milk drink, maximum concentrations were obtained at the same time (0.5-3.0 h) as with the reference tablet (0.5-4.0 h). Plasma peak concentrations appeared highest after the commercial tablet (mean +/- SD: Cmax 2.8 +/- 0.55 mg/l), but the difference to the effervescent tablet (2.7 +/- 0.41 mg/l) and the milk formulation (2.5 +/- 0.41 mg/l) was negligible. Similar mean elimination half-lives of 73, 77, and 77 h were obtained with the effervescent tablet, the milk drink, and the commercial tablet, respectively. Average bioavailability relative to the tablet was for the effervescent tablet and for the milk drink 96% with a coefficient of variation of 8%. The 90%-confidence intervals of the mean differences between the test and standard preparations in log-transformed AUC0-infinity and Cmax were within 20% around the respective mean parameter value calculated for the standard preparation allowing to conclude bioequivalence of the three oral formulations.

Mixed linear and non-linear disposition of lazabemide, a reversible and selective inhibitor of monoamine oxidase B.

1. Single oral doses (100-300 mg) and multiple oral doses (100-350 mg 12 hourly for 7 days) of lazabemide were administered to 35 young and 40 elderly healthy subjects. Plasma concentrations of unchanged drug were determined to study the dose-concentration relationship. 2. The elimination phase time course of lazabemide concentrations indicated concentration-dependent elimination after both single and multiple dosing. Nevertheless, maximum concentrations and areas under concentration-time curves increased almost proportionally with dose and accumulation after chronic dosing was less than a factor of 2; steady-state concentrations were achieved by the third day of dosing. The apparent half-life determining accumulation was approximately 8-9 h. 3. Drug absorption commenced rapidly after a dose; two components to the absorption process were detectable in young subjects possibly due to simultaneous administration of multiple tablets at the higher doses. 4. Observations after single and multiple dosing were described with a compartmental model allowing for parallel saturable (population mean +/- s.d.: maximum elimination rate Vmax/F: 2.8 +/- 1.4 mg h-1; concentration at half-maximum elimination Km: 36 +/- 19 micrograms l-1) and first-order (CL/F 16 +/- 3.8 l h-1) elimination pathways. No important difference between the young and the elderly subjects was noted in absorption or disposition parameters of lazabemide.

Pharmacodynamics of lazabemide, a reversible and selective inhibitor of monoamine oxidase B.

1. The inhibition of monoamine oxidase B (MAO-B) by lazabemide was measured in platelets collected from 35 young (19-36 years) and 40 older (60-78 years) healthy volunteers after single (100-300 mg) and multiple (100-350 mg twice daily) oral doses respectively. 2. The relationship of the effect with plasma concentrations of the MAO-B inhibitor was defined by a sigmoid Imax-model using either a parametric or semi-parametric method for predicting plasma drug concentrations. Population parameter estimates were obtained by the expectation maximization method and a standard two-stage method. 3. At the lowest dose platelet MAO-B activity was almost completely inhibited for around 20 h. No time delay between plasma drug concentration and resulting inhibition of platelet MAO-B occurred. Low concentrations of the inhibitor produced 50% of maximum inhibition (IC50, estimates for population mean +/- s.d.: 0.48 +/- 0.89 microgram l-1 for young and 1.5 +/- 2.3 micrograms l-1 for elderly subjects). The maximum extent of enzyme inhibition attributable to lazabemide (Imax) was 94 +/- 5.1% and 96 +/- 4.5% in the young and older populations. There was no correlation between age and either Imax or IC50. 4. Model parameters describing the interaction of lazabemide with the enzyme did not change over the treatment period of 7 days.

Monoamine oxidase-A: pharmacodynamics in humans of moclobemide, a reversible and selective inhibitor.

1. Single oral doses of 300, 450 and 600 mg moclobemide, a monoamine oxidase type A inhibitor, were administered in a cross-over design to eight healthy male volunteers. Plasma concentrations of the parent drug and of two monoamine metabolites (3,4-dihydroxyphenylglycol DHPG from noradrenaline; 5-hydroxy-indoleacetic acid 5HIAA from serotonin) were measured over time. 2. A physiological pharmacokinetic-pharmacodynamic model was used to describe MAO-A inhibition as reflected in the alterations of monoamine metabolites. Population values for the model parameters were obtained by a two-stage method allowing for repeated dosing per subject. 3. Even at the lowest dose an effect of moclobemide on plasma DHPG and 5HIAA concentrations was detectable in most subjects for up to 24 h. In contrast to DHPG, 5HIAA formation was only partially suppressed by moclobemide (maximum fractional extent of enzyme inhibition Imax: 0.57, CV 26%) suggesting the existence of 5HIAA formation pathways independent of those inhibitable by moclobemide. 4. Plasma moclobemide concentrations associated with 50% of maximum enzyme inhibition (IC50) were in the range of 100 (IC50,5HIAA at 300 mg) to 400 micrograms l-1 (IC50,DHPG at 600 mg).

Bioavailability of intramuscularly administered tenoxicam.

Bioavailability of intramuscularly administered tenoxicam relative to single oral and relative to intravenous doses was determined in two separate randomized crossover studies. Twelve healthy volunteers (12 males, age 20-30 years) received a rapid intravenous injection and a single intramuscular dose and 12 other subjects (11 males, 1 female, age 21-25 years) a single oral and a single intramuscular dose of 20 mg of tenoxicam on two different occasions. The wash-out period between the two consecutive treatments was 4 weeks. Plasma concentrations after dosing were determined by a specific HPLC method. Differences in tenoxicam concentration-time profiles after the different routes of administration were limited to the first 2 h after dosing. Later, plasma concentrations were almost superimposable within and across the two studies. The extent of absorption of intramuscularly administered tenoxicam was complete (mean +/- CV per cent: F(abs) 0.99 +/- 20 per cent) with no difference between the two extravascular administrations (F(rel) 0.95 +/- 10 per cent, intramuscular vs oral). After intramuscular administration tenoxicam was more rapidly absorbed compared to the oral dose (Tmax 0.71 h +/- 80 per cent vs 1.4 h +/- 62 per cent; p > 0.05). Peak concentrations after oral and intramuscular administration (Cmax 2.5 mg l-1 +/- 19 per cent vs 2.7 mg l-1 +/- 14 per cent; p < 0.05) were very similar.

Studies on the excretion of diazepam and nordazepam into milk for the prediction of milk-to-plasma drug concentration ratios.

The influence of varying protein and fat content in milk of New Zealand White rabbits on the milk-to-plasma drug concentration (M/P) ratio of diazepam was studied. At various time points after littering, a bolus dose (1.5 mg/kg) followed by a 26-hr infusion (1.8 mg/h) of diazepam was administered to freely moving rabbits via a jugular vein catheter. Milk and blood samples were collected to allow characterization of milk composition and quantitative determination of diazepam and nordazepam in milk and plasma. At steady state diazepam showed M/P ratios between 3.7 and 9.5, whereas nordazepam showed ratios between 2.1 and 4.3, respectively. The relative importance of milk protein binding and milk-fat partitioning for the excretion of a drug into milk depended on the drug's affinity to milk fat. A stepwise multiple regression analysis suggested that observed M/P ratios of diazepam could be explained by considering the fat content of milk alone. Nordazepam with a lower solubility in milk fat showed M/P ratios which could be best explained by considering protein and fat concentrations together. Using the data from the infusion studies, two recently published diffusional models to predict M/P ratios were evaluated. Neither model could accurately predict the M/P ratios of diazepam and nordazepam observed in rabbits. However, after extending the model described by Atkinson and Begg to take the actually measured partitioning between skim milk and milk fat into account, a great improvement in the predictive power for observed M/P ratios occurred.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of moclobemide in male, virgin female, pregnant and nursing rats.

The disposition of moclobemide, a reversible inhibitor of monoamine oxidase isoenzyme A was studied in male, virgin female, pregnant and nursing rats. The average clearance in control rats (male and female) was 36 mL min-1 kg-1, the initial volume of distribution 1.4 L kg-1, the volume of distribution at steady state 2.3 L kg-1 and the terminal half-life 59 min. The blood-to-plasma concentration ratio of moclobemide was 0.84 giving rise to an average blood clearance of 30 mL min-1 kg-1. The clearance values in rats were higher than in man but as a fraction of hepatic blood flow were similar (36 vs 45%). The volume of distribution at steady state was approximately twice as high as in man while the half-life was similar. Pregnant and nursing rats showed no statistically significant differences in their disposition parameters for moclobemide compared with virgin female rats. Nursing rats had statistically significantly lower concentrations of the moclobemide N-oxide metabolite than did pregnant and control rats. Generally lower concentrations of the lactam metabolite were also found in this group although the differences did not reach statistical significance. Moclobemide as well as the N-oxide and lactam metabolites were found in the amniotic fluid suggesting that moclobemide is capable of crossing the placental barrier.

Unaltered ibuprofen-induced faecal blood loss upon coadministration of moclobemide.

The influence of moclobemide on ibuprofen-induced faecal blood loss was investigated in 24 volunteers. The subjects were randomly assigned to one of two groups and received from day 1 until day 14 either moclobemide 150 mg t.i.d. (group A) or placebo t.i.d. (group B). On days 8-14, when moclobemide concentrations in group A were at steady state, all volunteers additionally received ibuprofen (600 mg t.i.d). From day 15 to 21, all subjects received placebo alone. Faecal blood loss (FBL) was quantified daily by the 51Cr-labelled erythrocyte method. As expected for ibuprofen, a significant increase in FBL during the second week of the study was observed. There was no difference in FBL between the two treatment groups (moclobemide or placebo). Similar FBL values were observed in both groups (group A vs B): during the first week the FBL values were (mean +/- SD) 0.40 +/- 0.23 ml/day vs 0.55 +/- 0.53 ml/day on days 1-3 and 0.40 +/- 0.21 ml/day vs 0.37 +/- 0.13 ml/day on days 4-7. The increase in FBL during the second week was comparable in both groups, with and without moclobemide (days 8-10: 0.78 +/- 0.59 ml/day vs 0.80 +/- 0.58 ml/day; days 11-14: 1.49 +/- 0.95 ml/day vs 1.28 +/- 0.62 ml/day). A decline in FBL was observed during the third week under placebo in both groups, but baseline values were not reached during the observation period. Again there was no difference between the two groups (days 15-17: 0.91 +/- 0.52 ml/day vs 0.92 +/- 0.47 ml/day; days 18-21: 0.74 +/- 0.30 ml/day vs 0.68 +/- 0.48 ml/day). No statistically significant interaction was found between week and type of treatment, indicating that no significant influence of moclobemide on the ibuprofen-induced faecal blood loss occurred. No notable pharmacokinetic interaction between moclobemide and ibuprofen was observed. Moclobemide plasma concentration-time profiles with and without concomitantly administered ibuprofen were superimposable. The results demonstrate that the concomitant administration of ibuprofen and moclobemide to healthy volunteers does not result in a clinically significant interaction, either at the pharmacodynamic (faecal blood loss) or at the pharmacokinetic level.

Determination of diazepam and nordazepam in milk and plasma in the presence of oxazepam and temazepam.

For studies on the excretion of drugs into milk a sensitive high-performance liquid chromatographic assay was developed to quantitate diazepam and nordazepam in the milk and plasma of humans and rabbits in the presence of their major metabolites, oxazepam and temazepam. Flurazepam was used as an internal standard. The assay involves extractions with diethyl ether and an additional acid clean-up step. Chromatographic separation was achieved by a LiChrospher 60 RP-select B (5 microns) column and KH2PO4- acetonitrile (69:31, v/v) adjusted to pH 2.80 as a mobile phase. The same extraction and chromatographic conditions were suited to both types of samples, milk and plasma. The limits of determination using ultraviolet detection at 241 nm was for diazepam 20 ng/ml and for nordazepam 15 ng/ml. The absolute recoveries of diazepam, nordazepam and flurazepam in human milk were 84, 86 and 92% and in human plasma 97, 89 and 94%, respectively. The within- and between-day accuracy and precision for diazepam and nordazepam in milk and plasma at all concentrations tested (20-1500 ng/ml) were better than 8%. The high fat content which occurs in rabbit milk presented no limitation for the extraction of lipophilic diazepam: the method was successfully used to monitor milk and plasma concentrations of diazepam and nordazepam in lactating New Zealand White rabbits during 26-h infusions of diazepam (1.4 mg/h).

Biopharmaceutical evaluation of carprofen following single intravenous, oral, and rectal doses in dogs.

Absorption and disposition characteristics of carprofen were compared in the dog after intravenous, oral, and rectal administrations. Rectal formulations included an aqueous solution and a suppository. Single doses of 100 mg carprofen were given in a cross-over design and plasma concentrations of unchanged drug were determined by HPLC. Plasma concentration-time profiles could be adequately described after intravenous and extravascular administrations by tri-and biexponential functions, respectively. After intravenous applications the basic disposition parameters could be determined: mean (+/- S.D.) elimination half-life was about 11.7 (+/- 3.1) h; volume of distribution ranged from 0.12 to 0.22 l kg-1 and total plasma clearance was about 0.017 +/- 0.003 l h kg-1. After oral dosing, carprofen was rapidly absorbed (time of maximum concentration: 0.83 +/- 0.61 h) and comparison with the intravenous solution indicated complete bioavailability. After rectal administration, the rate of absorption evaluated through tmax and calculation of mean absorption times was always slower than after oral dosing. Relative bioavailabilities of the drug from the suppository were about 20 per cent lower than from rectal solutions. No significant difference in rates of absorption of carprofen from rectal solution and suppository was seen; this allowed the conclusion that drug release from the semi-solid dosage form was not the rate-limiting step in carprofen absorption from the suppository. From the present study, it is concluded that rectal administration of carprofen offers an alternative to the oral route of drug intake.

A phase I study of doxifluridine as a five-day stepped-dose continuous infusion.

Doxifluridine (5'-dFUR) is a prodrug of 5 fluorouracil (5-FU) synthesized in an attempt to improve the therapeutic index compared with 5-FU. In this phase I study, cohorts of three patients were treated by a 5-day continuous infusion with the dose increased daily, total doses ranging from 3.75 g/m2 to 20 g/m2/120 h. Twenty-nine patients received 54 courses (median 2, range 1-4). The dose-limiting toxicities were mucositis (Miller grade 3 in three patients and grade 4 in another) and grade 4 neutropenia and thrombocytopenia in two patients. Other toxicities included nausea, vomiting, and diarrhea, rash, and fever. Neurological toxicity was mild and no cardiovascular toxicity was recorded. Plasma and urine levels of 5'-dFUR and 5-FU were quantitated by high-performance liquid chromatography. Steady-state plasma levels between 167 ng/ml and 6,519 ng/ml were recorded and at these levels there was no evidence of saturation of doxifluridine metabolism. One patient at the maximum tolerated dose of 20 g/m2/120 h had a complete response in a nasopharyngeal carcinoma.

Increase of plasma nonesterified fatty acid concentration and decrease of albumin binding affinity after intravenous injection of glycocholate-lecithin mixed micelles.

Lipophilic drugs intended for intravenous use can be solubilized by mixed-micellar systems containing glycoholic acid and lecithin (MM). Our present studies determined the influence of such MM preparations on albumin binding of monoacetyldiaminodiphenyl sulfone (MADDS), a deputy ligand for bilirubin. After intravenous administration of MMs to healthy male and female adult volunteers, concentration-time profiles of bile acid and nonesterified (NEFA) and esterified fatty acids were obtained as well. In vitro experiments with blood from adults and from neonatal cords indicated a modest reduction in reserve albumin for binding of MADDS after addition of MMs, resulting from glycocholic acid in the micellar preparation. After injection of MM preparations with up to 530 mg glycocholic acid, a rapid decrease of the reserve albumin was observed. The effect was more pronounced in men than in women and resulted in different areas under the time curve for the decrease (p = 0.049). At their maximum (3 to 10 minutes after MM doses) the decreases averaged (+/- SD) 68% +/- 14% in men and 45% +/- 8.5% in women. Low reserve albumin concentrations were maintained over 20 minutes despite rapidly declining bile acid concentrations. Injection of MM caused a drastic increase of NEFA in the serum samples with a more pronounced effect in men (average +/- SD increase: 473% +/- 93%) than in women (148% +/- 91%) (p = 0.01). The changes in NEFA concentrations ran reciprocal to the changes of reserve albumin for binding MADDS. In all subjects the increase in NEFA was accompanied by a decrease in reserve albumin for palmitate. Fatty acid binding to albumin was well restored within 1 hour. Thus, before drugs incorporated in MM can be prescribed to neonates who are at risk for having kernicterus, the impact of intravenous MM on bilirubin binding and NEFA levels must be investigated in that patient population.

Biopharmaceutical evaluation of ketoprofen following intravenous, oral, and rectal administration in dogs.

The influence of the hydrophilicity of three suppository bases on the rectal absorption of ketoprofen was studied. Absorption characteristics of ketoprofen were compared after intravenous, oral, and rectal administrations of 100 mg of drug given in a crossover design to five dogs. Rectal formulations included an aqueous solution and three suppository formulations. After oral dosing, ketoprofen was rapidly absorbed (time of maximum concentration, tmax: 0.83 +/- 0.61 h), and a comparison with the intravenous solution indicated a complete bioavailability of 0.90 +/- 0.10. After rectal administration, the rate of absorption, as evaluated with tmax and mean absorption time, was always slower than after oral dosing. A high variability was observed in the plasma concentrations obtained with suppository formulations; bioavailability values were approximately 20% lower than those from the oral solutions. No statistical difference in bioavailability and peak concentrations between the three suppository formulations was observed. Time of peak concentrations, mean absorption times, and fractions of the dose absorbed 6 h post administration did not show a difference in rate of ketoprofen absorption from the three suppository formulations. This study did not reveal a relationship between rate and extent of ketoprofen rectal absorption and the hydrophilicity of the suppository bases tested.