Search

Enoxacin decreases the metabolic clearance of the bronchodilator theophylline not only in severely ill patients, but also in patients with stable chronic obstructive airways disease. In this comparative study, significantly increased plasma theophylline concentrations were measured during co-administration of enoxacin (110.9%) and, to a lesser degree, also during co-administration of pefloxacin (19.6%) and ciprofloxacin (22.8%). Total body clearance of theophylline was significantly decreased by enoxacin (63.6%), ciprofloxacin (30.4%) and pefloxacin (29.4%). The pharmacokinetic parameters of theophylline did not change during co-administration of ofloxacin and nalidixic acid. There is growing evidence that the observed interaction is caused not by the parent drugs, but by the 4-oxo metabolite of enoxacin, pefloxacin and ciprofloxacin. [ABSTRACT FROM AUTHOR]

In patients treated concurrently with theophylline and enoxacin, a new broad-spectrum antibacterial agent of the quinolone class, unexpectedly high plasma theophylline concentrations were measured. In part I of this study, daily plasma theophylline concentrations were measured in 14 patients. The mean +/- s.d. theophylline concentrations increased from 8.5 +/- 2.8 micrograms ml-1 prior to enoxacin to a maximum of 21.7 +/- 7.8 micrograms ml-1 during coadministration. In part II, six of these patients received aminophylline intravenously at a constant infusion rate and under controlled conditions. Plasma theophylline concentrations rose from 8.4 +/- 2.4 micrograms ml-1 prior to enoxacin treatment to 15.0 +/- 5.1 micrograms ml-1 at day 3 of coadministration (P less than 0.005). Plasma protein-binding and renal clearance of theophylline remained unchanged, whereas total body clearance of theophylline significantly decreased (P less than 0.005). From these observations it is concluded that the rise of plasma theophylline concentrations is caused by a reduced metabolic clearance of theophylline. If concomitant use of both drugs is necessary, monitoring of plasma theophylline concentration and adjustment of the theophylline dose is recommended. [ABSTRACT FROM AUTHOR]

1 The clinical pharmacokinetics of the many benzodiazepines used to treat numerous and varied clinical conditions can be influenced by many factors. 2 Combinations of drugs efficacious in the central nervous system can change the onset, intensity and duration of effect as a result of pharmacological, physiological and pharmacokinetic actions. 3 Pharmacokinetic considerations indicate that short to medium long- acting benzodiazepines that depend on only glucuronidation for their major metabolic pathway are the drugs of choice in this category. [ABSTRACT FROM AUTHOR]

Aims: No pharmacokinetic data exist on doses of ropivacaine larger than 300 mg for peripheral nerve block in man, although in clinical practice higher doses are frequently used. The purpose of the present study was to describe the pharmacokinetic profile in serum of 450 mg ropivacaine with and without epinephrine in patients undergoing anterior cruciate ligament reconstruction., Methods: Twelve patients were randomly allocated to receive a single shot combined sciatic/femoral nerve block with 60 ml of either ropivacaine 0.75% alone (group R, n = 6) or ropivacaine 0.75% plus epinephrine 5 μg ml(-1) (group RE, n = 6). Venous blood samples for total and free ropivacaine serum concentrations were obtained during 48 h following block placement. Pharmacokinetic parameters were calculated using a non-compartmental approach., Results: Results are given as mean (SD) for group R vs. group RE (95% CI of the difference). Total Cmax was 2.81 (0.94) μg ml(-1) vs. 2.16 (0.21) μg ml(-1) (95% CI -0.23, 1.53). tmax was 1.17 (0.30) h vs. 1.67 (0.94) h (95% CI -1.40, 0.40). The highest free ropivacaine concentration per patient was 0.16 (0.08) μg ml(-1) vs. 0.12 (0.04) μg ml(-1) (95% CI -0.04, 0.12). t(1/2) was 6.82 (2.26) h vs. 5.48 (1.69) h (95% CI -1.23, 3.91). AUC was 28.35 (5.92) μg ml(-1)  h vs. 29.12 (7.34) μg ml(-1)  h (95% CI -9.35, 7.81)., Conclusions: Free serum concentrations of ropivacaine with and without epinephrine remained well below the assumed threshold of 0.56 μg ml(-1) for systemic toxicity. Changes in pharmacokinetics with epinephrine co-administration did not reach statistical significance., (© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.)

Quicker onset and shorter elimination time favours (+/-) articaine as a short-acting local anaesthetic for regional anaesthesia in day-case settings, e.g. arthroscopy (shoulder, knee), hand and foot surgery, and dentistry, because patients treated with articaine will be 'drug free' more quickly than those who receive other local anaesthetics. Articaine diffuses better through soft tissue and bone than other local anaesthetics. The concentration of articaine in the alveolus of a tooth in the upper jaw after extraction was about 100 times higher than that in systemic circulation. Articaine is metabolised via hydrolysis into articainic acid, 75% of which in turn is excreted as such and 25% in the glucuronidated form by the kidneys. The half-lives of elimination (t1/2alpha and t1/2beta) of articaine are 0.6 and 2.5 hours, whereas the apparent half-life of the metabolite articainic acid is 2.5 hours. Intrinsic half-lives of articainic acid are: t1/2alpha 12 minutes, and t1/2beta 64 minutes (1 hour). In dentistry, articaine is the drug of choice in the vast majority of literature. In other regional anaesthesia techniques (intravenous regional anaesthesia, epidural, spinal and plexus blocks) there are not enough data to prove that (+/-) articaine is safer and more effective than the short-acting local anaesthetics lidocaine, (+/-) prilocaine or (+/-) mepivacaine.

High concentrations of enterolignans in plasma are associated with a lower risk of acute coronary events. However, little is known about the absorption and excretion of enterolignans. The pharmacokinetic parameters and urinary excretion of enterodiol and enterolactone were evaluated after consumption of their purified plant precursor, secoisolariciresinol diglucoside (SDG). Twelve healthy volunteers ingested a single dose of purified SDG (1.31 micromol/kg body wt). Enterolignans appeared in plasma 8-10 h after ingestion of the purified SDG. Enterodiol reached its maximum plasma concentration 14.8 +/- 5.1 h (mean +/- SD) after ingestion of SDG, whereas enterolactone reached its maximum 19.7 +/- 6.2 h after ingestion. The mean elimination half-life of enterodiol (4.4 +/- 1.3 h) was shorter than that of enterolactone (12.6 +/- 5.6 h). The mean area under the curve of enterolactone (1762 +/- 1117 nmol/L . h) was twice as large as that of enterodiol (966 +/- 639 nmol/L . h). The mean residence time for enterodiol was 20.6 +/- 5.9 h and that for enterolactone was 35.8 +/- 10.6 h. Within 3 d, up to 40% of the ingested SDG was excreted as enterolignans via urine, with the majority (58%) as enterolactone. In conclusion, a substantial part of enterolignans becomes available in the blood circulation and is subsequently excreted. The measured mean residence times and elimination half-lives indicate that enterolignans accumulate in plasma when consumed 2-3 times a day and reach steady state. Therefore, plasma enterolignan concentrations are expected to be good biomarkers of dietary lignan exposure and can be used to evaluate the effects of lignans.

Objective: To identify differences in the disposition of isosorbide-5-mononitrate between male and female volunteers., Method: Plasma concentration and area under the concentration-time curve (AUC(SS)) data of isosorbide-5-mononitrate were obtained in a randomized, crossover, multiple-dose bioequivalence study in 24 subjects (12 females and 12 males). Participants received a single oral dose of 60 mg isosorbide-5-mononitrate prolonged-release tablet formulation (formulations I and II) on each of 6 consecutive days. Plasma isosorbide-5-mononitrate concentrations were determined according to validated methods involving liquid chromatography mass spectrometry., Results: A total of 2 x 24 plasma concentration-time curves of the parent drug could be analyzed. The intersubject variation in plasma concentrations ranged from 25-50% (coefficient of variation). With both formulations, the mean plasma concentration-time curves for males and females ran parallel. The parameters Cmax, Cmin, AUC(SS), and AUC(SS)/kg in females were significantly higher than in males (p < 0.0001). This difference was solely attributed to the difference in body weight (p = 0.0024) and body mass index between males and females (p = 0.0113). Seven females showed a t = 0 = 24 h (Cmin) plasma concentration that was twice as high as the other 5 females and all the males; 125 +/- 12.2 ng/ml versus 59.3 +/- 9.2 ng/ml, respectively, in females (p < 0.0001) and 56.3 +/- 6.9 ng/ml in males (p < 0.0001). With both formulations, females in the n = 7 group had a longer t(1/2) and MRT than females in the n = 5 group, 5.06 +/- 0.76 h, 11.2 +/- 0.55 h versus 4.19 +/- 0.56, 9.40 +/- 0.62 h (p = 0.0057). The male group did not show this phenomenon, their disposition was similar to that of the female group of n = 5., Conclusion: The difference found in the Cmax and AUC(SS)/kg of isosorbide-5-mononitrate between male and female subjects must be due to the difference in dose/kg, following a standard dose of 60 mg. Fixed dose administration is common practice due to the available pharmaceutical formulations, while in the ideal situation the dose should be based on dose/kg or titrated to the required clinical effect.

The objective of this study was to identify differences in disposition and esterase hydrolysis of ramipril between male and female volunteers. Plasma concentration and area under the concentration-time curve until the last measured concentration (AUCt) data of ramipril and its active metabolite ramiprilat (-diacid) were obtained from a randomised, cross-over bioequivalence study in 36 subjects (18 females and 18 males). Participants received a single 5-mg oral dose of two different formulations of ramipril (Formulation I and II). Plasma ramipril and ramiprilat concentrations were determined according to validated methods involving liquid chromatography-mass spectrometry. A total number of 2 x 34 available plasma concentration-time curves of both the parent drug and the metabolite could be analysed, and variations (50-100% coefficient of variation [CV]) in plasma concentrations of both parent drug and metabolite were found. With both the formulations, the mean plasma concentrations-time curves of males and females were identical. The groups of female and male volunteers showed similar yields (AUCt = microg x h/L) of the metabolite ramiprilat (p = 0.37); however, females showed a higher AUCt/kg than males (p = 0.046). This difference was solely attributed to the difference in body weight between males and females (p = 0.00049). In both male and female groups, a subject-dependent yield of active metabolite ramiprilat was demonstrated, which was independent of the formulation. There is a large variation in the ramiprilat t1/2beta (50-60% CV). There is a group of subjects who showed a t1/2beta of approximately 80 h (15% CV), and two apparent groups with a longer t1/2beta for each formulation (124 h, 22.5% CV; 166 h, 21.6% CV, respectively, p = 0.0013). This variation in the terminal half-life of ramiprilat is not sex related. In all three groups of half-lives, the corresponding Cmax values (mean +/- SD) of ramiprilat in males and females were identical. Thus, with identical Cmax and half-lives, the difference found in the AUCt/kg of ramiprilat must be due to the difference in dose, as the consequence of the difference in body weight, following a standard dose of 5 mg in both males and females. This study showed clearly that despite subject-dependent hydrolysis of ramipril to the active metabolite ramiprilat, the variability in the rate of hydrolysis between males and females is similar. With a fixed dose (5 mg), females received a higher dose/kg than males and consequently showed a higher AUCt/kg of the active metabolite ramiprilat.

The aim of this pharmacokinetic evaluation was to show the effect of the extra methyl group in simvastatin on esterase hydrolysis between lovastatin and simvastatin in male and female volunteers. This study was based on the plasma concentration-time curves and the pharmacokinetics of lovastatin and simvastatin with its respective active metabolite statin-beta-hydroxy acid obtained from two different bioequivalence studies, each with 18 females and 18 males. Results were: The group of female volunteers showed a higher yield of the active metabolite beta-hydroxy acid than the group of males (p < 0.002) for both lovastatin and simvastatin. This difference was not related to the body weight of both groups. In the male/female groups, subject-dependent yield of active metabolite beta-hydroxy acid was demonstrated, which was independent of the formulation. The variation in plasma/liver hydrolysis resulted in a fan-shaped distribution of data points when the AUCt lovastatin was plotted vs. that of the beta-hydroxy acid metabolite. In the fan of data points, subgroups could be distinguished, each showing a different regression line and with a different Y-intercept (AUCtbeta-hydroxy acid). Lovastatin hydrolysis was higher than simvastatin hydrolysis. It was possible to discriminate between hydrolysis of both lovastatin and simvastatin by plasma/liver or tissue esterase activity. The three subgroups of subjects (males/females) showing different but high yield of statin beta-hydroxy acid can be explained by variable hydrolysis of plasma and hepatic microsomal and cytosolic carboxyesterase activity. This study showed clearly that despite the subject-dependent hydrolysis of lovastatin/simvastatin to the active metabolite, males tend to hydrolyse less than females. The extra methyl group in simvastatin results in less hydrolysis due to steric hindrance.

The aims of this investigation were to calculate the pharmacokinetic parameters and to identify parameters, based on individual plasma concentration-time curves of amoxicillin and clavulanic acid in dogs, that may govern the observed differences in absorption of both drugs. The evaluation was based on the data from plasma concentration-time curves obtained following a single dose in an open, randomized, two-way crossover study involving 24 male Beagle dogs treated with two Amoxi-Clav formulations (A Clavubactin and B Synulox, each with 200/50 mg). Plasma amoxicillin and clavulanic acid concentrations were determined using validated bioassay methods. The half-life of elimination of amoxicillin was 1.5 h (t1/2 = 1.52 +/- 0.19 h, Cmax = 11.4 +/- 2.74 microg/mL), and that of clavulanic acid 0.76 h (t1/2 = 0.71 +/- 0.23 h, Cmax = 2.06 +/- 1.05 microg/mL). There was a fivefold variation in the AUCt of clavulanic acid for both formulations, while the AUCt of amoxicillin varied by a factor of 2. The mean ratio of the AUCt amoxicillin : clavulanic acid was 12.7 +/- 3.65 for formulation A and 11.8 +/- 5.22 for formulation B (P = 0.51).

Objectives: Fracture of the upper femur is a common injury in the elderly. Several anesthetic techniques exist for surgery of traumatic hip fracture. The aim of this investigation was to study plasma concentrations and safety of 2 mg/kg bupivacaine in a femoral "3-in-1" nerve block in patients older than 80 years of age., Subjects and Methods: A 3-in-1 femoral nerve block, combined with a general anesthetic was used in 10 elderly patients aged over 80 years. They were undergoing emergency surgery for stabilization of their fractured femur. Bupivacaine plasma concentrations of radial artery blood samples were assessed over a 6-hour period after a femoral 3-in-1 injection of 2 mg/kg bupivacaine 0.375% with epinephrine (1:400,000)., Results: No toxic reactions to bupivacaine were seen. In 8 of the 10 patients per- and postoperative analgesia were adequate as a result of the nerve block. Patients experienced loss of sensation and analgesia for 26.6 +/- 4.6 hours (mean +/- SD). This was inversely related to the apparent steady state concentration of bupivacaine. The mean of the individual peak plasma concentrations of bupivacaine (C(max) was 0.74+/- 0.64 microg/ml. The highest plasma concentration was 1.83 microg/ml. Large variations in plasma concentrations were detected in these patients. Bupivacaine metabolites were not detected., Conclusions: A femoral 3-in-1 nerve block, using 2 mg/kg bupivacaine with epinephrine, provides prolonged pain reliefwithout local anesthetic toxicity in elderly patients. It is a satisfactory supplementary analgesic technique for hip and knee surgery in the elderly.

The aims of this investigation were to calculate the pharmacokinetic parameters of amoxicillin and clavulanic acid, and to identify parameters that may affect their observed differences in absorption. Data were obtained from plasma concentration-time curves from four different open, randomized, two-treatment, two-period, two-sequence, crossover Phase I bioequivalence studies, with the following co-amoxiclav formulations: tablets 250/125, 500/125 and 875/125 mg, or 10 mL of an oral suspension 250/62.5 mg per 5 mL. Data from 144 subjects and 288 drug administrations were available for evaluation. After a 125 mg clavulanic acid dose (administered as potassium clavulanate) for all four different formulations, the clavulanic acid AUC(t) data ranged from 1.5 to 8 mg.h/L, varying by a factor of 5. The absorption of clavulanic acid was not related to the absorption of amoxicillin, or demographic factors, and we were unable to identify the reasons for the large variability in the absorption of clavulanic acid. We conclude that the absorption of clavulanic acid, after oral administration, is highly variable and may vary over a five-fold range between patients.

The aims of this investigation were to calculate the pharmacokinetic parameters and to identify parameters, based on individual plasma concentration-time curves of amoxicillin and clavulanic acid in cats, that may govern the observed differences in absorption of both drugs. The evaluation was based on the data from plasma concentration-time curves obtained following a single-dose, open, randomised, two-way crossover phase-I study, each involving 24 female cats treated with two Amoxi-Clav formulations (formulation A was Clavubactin and formulation was B Synulox; 80/20 mg, 24 animals, 48 drug administrations). Plasma amoxicillin and clavulanic acid concentrations were determined using validated bioassay methods. The half-life of elimination of amoxicillin is 1.2 h (t1/2 = 1.24 +/- 0.28 h, Cmax = 12.8 +/- 2.12 microg/ml), and that of clavulanic acid 0.6 h (t1/2 = 0.63 +/- 0.16 h, Cmax = 4.60 +/- 1.68 microg/ml). There is a ninefold variation in the AUCt of clavulanic acid for both formulations, while the AUCt of amoxicillin varies by a factor of two. The highest clavulanic acid AUCt values indicate the best absorption; all other data indicate less absorption. Taking into account that the amoxicillin-to-clavulanic acid dose ratio in the two products tested was 4:1, the blood concentration ratios may actually vary much more, apparently without compromising the products" high efficacy against susceptible microorganisms.

The aim of this investigation was to compare the clinical effects and pharmacokinetics of lidocaine (one metabolite) and mepivacaine (two metabolites) in 2 groups of 15 patients undergoing axillary brachial plexus anaesthesia. The study had a randomised design. The 30 patients were divided into 2 groups. The patients received either lidocaine (600 mg = 2.561 mMol + 5 mg ml(-1) adrenaline) or mepivacaine (600 mg = 2.436 mMol + 5 microg ml(-1) adrenaline), injected via the axilla near the brachial plexus over a period of 30 s. Onset of surgical analgesia was defined as the period from the end of the local anaesthetic injection to the loss of pinprick sensation in the distribution of the ulnar, radial, and median nerve. Motor block was measured. Onset of motor block was similar for both drugs. Lidocaine is eliminated biexponentially with a t1/2alpha of 9.95 +/- 14.3 min and a t1/2beta of 2.86 +/- 1.55 h. Lidocaine is metabolised into MEGX (tmax 2.31 +/- 0.84 h; Cmax 0.32 +/- 0.13 mg l(-1); t1/2beta 2.36 +/- 2.35 h; total body clearance was 67.9 +/- 28.9 l h(-1)). Mepivacaine is eliminated rapidly and monoexponentially with a t1/2 of 4.78 +/- 2.38 h, a Cmax of 3.89 +/- 0.83 mg l(-1), and a tmax of 0.41 +/- 0.19 h. The total body clearance of mepivacaine is 50% of that of lidocaine, 26.9 +/- 10.6 l h(-1) vs. 67.9 +/- 28.9 l h-1, respectively (p < 0.0001). (+/-)mepivacaine is metabolised into (+/-)4-OHmepivacaine (Cmax 0.45 +/- 0.25 mg l(-1); t1/2beta 6.48 +/- 6.57 h) and (+/-)2,6-pipecoloxylidide (Cmax 0.56 +/- 0.30 mg l(-1); t1/2beta 1.48 +/- 0.74 h). For the axillary brachial plexus block, lidocaine and mepivacaine show similar pharmacodynamic and pharmacokinetic behaviour, despite the number of metabolites, and can therefore be used to the clinical preference for this regional anaesthetic technique.

Aim: The aim of this investigation was to identify which part of a dose mesalazine is acetylated by enzymes in the gut wall during the absorption process, and which part by the liver enzymes after absorption., Method: This study was based on data from four bioequivalence studies of different formulations of tablets (gastro-resistant single dose 500 mg (n = 24) and prolonged-release tablets (single dose 1000 mg, n = 18; multiple dose 1000 mg t.i.d. six days n = 28), suppositories (single 500 mg dose, n = 24) and a study with two i.v. administrations of 100 and 250 mg mesalazine (n = 6). In total, 200 administrations were carried out and plasma concentration-time curves obtained and analyzed. There was a large variability in the absorption of mesalazine for all formulations. The plasma concentration-time curves of parent drug and metabolite acetylmesalazine run nearly parallel, independent of the formulation and the dose. Plasma and urine mesalazine and acetylmesalazine concentrations were determined according to validated methods using HPLC analysis with coulometric or mass-spectrometric detection., Results: As a result of the large variations in release and absorption of mesalazine in the pharmaceutical formulations and administrations, it was possible to demonstrate that acetylation occurs in the gut wall and in the liver. By comparing oral and rectal data to intravenous data, it was possible to indicate where (and to what extent) acetylation occurs in the gut wall, in the liver, or both. Rectal administration of a mesalazine suppository and intravenous administration results in hepatic acetylation. Oral administrations of mesalazine results in both gut wall and hepatic acetylation. Acetylation by the gut wall amounts to 30% of the dose for gastroresistant tablets and to 40% of the dose for prolonged-release tablets.

Muscle relaxants can be safely administered during anaesthesia, providing the basic pharmacodynamic and pharmacokinetic characteristics of the compounds together with the physiological status of the patient are known. In this review the pharmacodynamics and pharmacokinetics of the neuromuscular blocking agents are discussed and related to the physical health or disease state of groups of patients.

Eighty per cent of codeine is conjugated with glucuronic acid to codeine-6-glucuronide. Only 5% of the dose is O-demethylated to morphine, which in turn is immediately glucuronidated at the 3- and 6-position and excreted renally. Based on the structural requirement of the opiate molecule for interaction with the mu-receptor to result in analgesia, codeine-6-glucuronide in analogy to morphine-6-glucuronide must be the active constituent of codeine. Poor metabolisers of codeine, those who lack the CYP450 2D6 isoenzyme for the O-demethylation to morphine, experience analgesia from codeine-6-glucuronide. Analgesia of codeine does not depend on the formation of morphine and the metaboliser phenotype.

This study was based on data from a bioequivalence study (n=24) of two different formulations of suppositories containing 500 mg mesalazine (formulation I and II), with a similar dissolution profile in phosphate buffer pH 6.8. There was a large intra- and intersubject variability in the plasma concentration-time curves of mesalazine from both suppositories. The aim of the investigation was to identify the parameters that caused the observed large variations in release and absorption of mesalazine in the rectum. Plasma mesalazine and acetylmesalazine, and urine acetylmesalazine concentrations were determined according to validated methods involving HPLC analysis with coulometric detection. Lower limit of quantitation values were respectively 10.4 and 19.4 ng mL(-1) in plasma and 0.96 microg mL(-1) in urine. The time of defecation before and after insertion was recorded. There was a clear distinction between subjects who showed monophasic mesalazine release/absorption and those who showed biphasic and more extended release/absorption. With formulation I there was a correlation between time of defecation before dosing and the type of absorption, monophasic and biphasic absorbers showed a significant difference in the time of defecation, e.g. 9.7+/-5.6 h vs 18.8+/-11.9 h (P = 0.0218). The impact of time of defecation before dosing was non-significant with formulation II, 16.7+/-7.2 h vs 15.1+/-4.2 h (P = 0.67). The impact of the time elapsed between administration and time of defecation after the insertion of the suppository was not significant for the type of release/absorption. The plasma concentration-time curves of the metabolite ran parallel to that of the parent drug, the more parent drug was released/absorbed, the more was acetylated (P = 0.0013) and excreted into the urine (P = 0.0004). After absorption the compound was metabolized into acetylmesalazine, and renally excreted (12-13% of the dose). Monophasic release/ absorption resulted in 7.1% metabolite with I and 10.3% with II (P = 0.0004), while biphasic release/absorption gave 16.8% metabolite with I and 15.5% with II. The renal clearance of the metabolite acetylmesalazine was independent of the observed defecation patterns (300 mL min(-1), P > 0.8), stool composition, and type of absorption.

The flavonoid quercetin is an antioxidant which occurs in foods mainly as glycosides. The sugar moiety in quercetin glycosides affects their bioavailability in humans. Quercetin-3-rutinoside is an important form of quercetin in foods, but its bioavailability in humans is only 20% of that of quercetin-4'-glucoside. Quercetin-3-rutinoside can be transformed into quercetin-3-glucoside by splitting off a rhamnose molecule. We studied whether this 3-glucoside has the same high bioavailability as the quercetin-4'-glucoside. To that end we fed five healthy men and four healthy women (19-57 y) a single dose of 325 micromol of pure quercetin-3-glucoside and a single dose of 331 micromol of pure quercetin-4'-glucoside and followed the plasma quercetin concentrations. The bioavailability was the same for both quercetin glucosides. The mean peak plasma concentration of quercetin was 5.0+/-1.0 micromol/L (+/-SE) after subjects had ingested quercetin-3-glucoside and 4.5+/-0.7 micromol/L after quercetin-4'-glucoside consumption. Peak concentration was reached 37 +/-12 min after ingestion of quercetin-3-glucoside and 27+/-5 min after quercetin-4'-glucoside. Half-life of elimination of quercetin from blood was 18.5+/-0.8 h after ingestion of quercetin-3-glucoside and 17.7+/-0.9 h after quercetin-4'-glucoside. We conclude that quercetin glucosides are rapidly absorbed in humans, irrespective of the position of the glucose moiety. Conversion of quercetin glycosides into glucosides is a promising strategy to enhance bioavailability of quercetin from foods.

Aim: The aim of this investigation was to compare the clinical effects and pharmacokinetics of lidocaine and articaine in two groups of 15 patients undergoing axillary brachial plexus anesthesia., Method: The study had a randomized design. Thirty patients were allocated to one of the two groups. Each patient received either lidocaine (600 mg = 2.561 mMol + 5 microg/ml adrenaline) or articaine (600 mg = 2.113 mMol + 5 microg/ml adrenaline), injected via the axilla of the brachial plexus over a period of 30 seconds. Onset of surgical analgesia was defined as the period from the end of the injection of the local anesthetic to the loss of pinprick sensation in the distribution of all three nerves., Results: The mean onset time of sensory block of the median nerve of both lidocaine and articaine were approximately 10 min. Lidocaine is biexponentially eliminated with a t1/2alpha of 9.95 +/- 14.3 min and a t1/2beta of 2.86 +/- 1.55 h. Lidocaine is metabolized into MEGX (mono-ethyl-glycyl-xilidide) (t(max) 2.31 +/- 0.84 h; C(max) 0.32 +/- 0.13 mg/l; t1/2beta 2.36 +/- 2.35 h). Lidocaine total body clearance was 67.9 +/- 28.9 l/h. Articaine is rapidly and monoexponentially eliminated with a t1/2beta of 0.95 +/- 0.39 h. The total body clearance of articaine is higher than that of lidocaine, 1,133 +/- 582 l/h vs 67.9 +/- 28.9 l/h, respectively (p < 0.0001). The volume of distribution (V(d)), of articaine is a factor 16 higher times than that of lidocaine (p < 0.0001)., Conclusion: For the axillary administration, lidocaine and articaine show similar pharmacodynamics with a different pharmacokinetic behavior and can therefore be used to the clinical preference for this regional anesthetic technique.

Fourteen metabolites of methylprednisolone have been analysed by gradient-elution high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS). The compounds were separated on a Cp Spherisorb 5 microm ODS column connected to a guard column packed with pellicular reversed phase. The mobile phase was an acetonitrile- 1.0% aqueous acetic acid gradient at a flow rate of 1.5 mL min(-1) The analysis gave a complete picture of parent drug, prodrugs and metabolites, and the alpha/beta stereochemistry was resolved. The short (1-2 h) elimination half-life of methylprednisolone is explained by extensive metabolism. The overall picture of the metabolic pathways of methylprednisolone is apparently simple-reduction of the C20 carbonyl group and further oxidation of the C20,C21 side chain (into C21COOH and C20COOH), in competition with or in addition to oxidation at the C6 position.

A gradient eluent HPLC analysis in human plasma and urine was developed and validated for methylprednisolone (MP), its prodrug methylprednisolone-21-hemisuccinate (MPS) with the metabolites 6beta-hydroxy-6alpha-methylprednisolone (MPA), 20-hydroxymethylprednisolone (MPC), 6beta-hydroxy-20alpha-hydroxymethylprednisolone (MPB), 6beta-hydroxy-20beta-hydroxymethylprednisolone (MPE), 20-carboxymethylprednisolone (MPD), methylprednisolone-glucuronide (MPF) and 21-carboxymethylprednisolone (MPX). The column was Cp Spherisorb C8 5 microm, 250 mm x 4.6 mm I.D. (Chrompack, Bergen op Zoom, The Netherlands) with a guard column 75 mm x 2.1 mm, packed with pellicular reversed-phase. The eluent was a mixture of acetonitrile and 0.067 M KH2PO4 buffer, pH 4.5. At t=O, the eluent consisted of 2% acetonitrile and 98% buffer (v/v). Over the following 35 min the eluent changed linearly until it attained a composition of 50% acetonitrile and 50% buffer (v/v). At 37 min (t=37) the eluent was changed over 5 min to the initial composition, followed by equilibration over 3 min. The flow-rate was 1.5 ml/min and UV detection was achieved at 248 nm. Preliminary pharmacokinetic data were obtained from one patient who showed illustrative plasma concentration-time curves and renal excretion-time profiles after a short-lasting infusion (0.5 h) of 1 g of methylprednisolone hemisuccinate. The half-life of prodrug methylprednisolone-21-hemisuccinate (MPS) was 0.3 h, that of metabolite MPX (21-carboxy MP) was 0.4 h and that of the parent drug methylprednisolone (MP) was 1.4 h. The half-lives of the metabolites are almost similar (4 h). The main compounds in the urine are methylprednisolone hemisuccinate (prodrug, 15.0%), methylprednisolone (parent drug, 14.6%), metabolite MPD (20-carboxy, 11.7%), and metabolite MPB (13.2%). The renal clearance values of metabolites MPB, MPC and MPD are approximately 500 ml/min, that of MP is 100 ml/min.

Aim: The aim of the study was to determine the absolute bioavailability and pharmacokinetics after a single dose oral administration in comparison to i.v. administration of 14C-labelled distigmine-bromide (14C-Ubretid) in healthy male volunteers., Results: After the intravenous administration, distigmine is eliminated from the body by renal excretion (85%), and for a small fraction by biliary excretion in the feces (4%). This situation is reversed after an oral administration, where 6.5% of the dose is recovered from the urine and 88% from the feces. This means that distigmine after oral administration is hardly absorbed, the calculated bioavailability is 4.65%., Conclusion: The mean absorption time (MAT) after oral administration was 10 h, influencing the t(1/2alpha) (1.4 vs 4.5 h) and the t(1/2beta) (60 vs 70 h) to higher values than after the i.v. administration (p < 0.05).

In the present study metabolites of methylprednisolone were detected using gradient elution high-performance liquid chromatography. Separation was performed by a Cp Spherisorb ODS 5 microm (250 mmx4.6 mm I.D.) column, connected to a guard column, packed with pellicular reversed phase. The mobile phase was a mixture of acetonitrile and 1% acetic acid in water. At t = 0, this phase consisted of 2% acetonitrile and 98% acetic acid 1% in water (v/v). During the following 35 min the phase changed linearly until it attained a composition of acetonitrile-buffer (50:50, v/v). At 40 min (t = 40) the mobile phase was changed over 5 min to the initial composition, followed by equilibration during 2 min. The flow-rate was 1.5 ml/min. UV detection was achieved at 248 nm. We have isolated the respective compounds with the most abundant concentration and suggested their chemical structure based on NMR, IR, UV, MS, retention behaviour and melting points. The c/, stereochemistry could not be solved in this study. The overall picture of the metabolic pathways of methylprednisolone is apparently simple: reduction of the C20 carbonyl group and further oxidation of the C20-C21 side chain (into C21-COOH and C20-COOH), in competition with or additional to the oxidation at the C6-position.

This review discusses the possibility of whether furosemide acyl glucuronide, a metabolite of furosemide, contributes to the clinical effect of diuresis. First an analytical method (e.g. HPLC) must be available to measure both parent drug and furosemide acyl glucuronide. Then, with correctly treated plasma and urine samples (light protected, pH 5) from volunteers and furosemide-treated patients, the kinetic curves of both furosemide as well as its acyl glucuronide can be measured. The acyl glucuronide is formed in part by the kidney tubules and it is possible that the compound is pharmacologically active through inhibition of the Na+/2Cl-/K+ co-transport system; up to now the mechanism of action has been solely attributed to furosemide. The total body clearance of furosemide occurs by hepatic and renal glucuronidation (50%) and by renal excretion (50%). Enterohepatic cycling of furosemide acyl glucuronide, followed by hydrolysis, results in a second and slow elimination phase with a half-life of 20-30 h. This slow elimination phase coincides with a pharmacodynamic rebound phase of urine retention. After each dosage of furosemide, there is first a short stimulation of urine flow (4 h), which is followed by a 3-day recovery period of the body. The following clinical implications arise from study of the elimination kinetics of furosemide. Repetitive dosing must result in accumulation of the recovery period. Accumulation of furosemide and its acyl glucuronide in patients with end-stage renal failure results from infinite hepatic cycling. Impaired kidney function may result in impaired glucuronidation and diuresis. While kidney impairment normally requires a dose reduction for those compounds which are mainly eliminated by renal excretion, for diuretics, a dose increment is required in order to maintain a required level of diuresis. The full clinical impact of the accumulation of furosemide and its acyl glucuronide in patients with end-stage renal failure has to be determined.

Propofol (P) is metabolized in humans by oxidation to 1,4-di-isopropylquinol (Q). P and Q are in turn conjugated with glucuronic acid to the respective glucuronides, propofol glucuronide (Pgluc), quinol-1-glucuronide (Q1G) and quinol-4-glucuronide (Q4G). Propofol and quinol with their glucuronide conjugates can be measured directly by gradient high-performance liquid chromatographic analysis without enzymic hydrolysis. The glucuronide conjugates were isolated by preparative HPLC from human urine samples. The glucuronides of P and Q were present in plasma and urine, P and Q were present in plasma, but not in urine. Quinol in plasma was present in the oxidised form, the quinone. Calibration curves of the respective glucuronides were constructed by enzymic deconjugation of isolated samples containing different concentrations of the glucuronides. The limit of quantitation of P and quinone in plasma are respectively 0.119 and 0.138 microg/ml. The limit of quantitation of the glucuronides in plasma are respectively: Pgluc 0.370 microg/ml, Q1G 1.02 microg/ml and Q4G 0.278 microg/ml. The corresponding values in urine are: Pgluc 0.264 microg/ml, Q1G 0.731 microg/ml and Q4G 0.199 microg/ml. A pharmacokinetic profile of P with its metabolites is shown, and some preliminary pharmacokinetic parameters of P and Q glucuronides are given.

Ergot alkaloids are well known preparations. Ergot alkaloids used in obstetrics and gynaecology are ergometrine (ergonovine; EM), methylergometrine (methergine; ME) and bromocriptine. The pharmaceutical properties of ME EM) are critical. To guarantee stability, ME and EM ampoules should be stored in a cool, dark place. ME and EM tablets are unstable in all conditions and they show an unpredictable bioavailability, which prevents oral use of the drugs for any purpose. ME and EM are known for their strong uterotonic effect and, compared with other ergot alkaloids, for their relatively slight vasoconstrictive abilities. ME and EM do have a place in the management of the third stage of labour as they are strong uterotonics. They act differently from oxytocin and prostaglandins, and have different adverse effects. Oxytocin should be used as prophylaxis or a the drug of first choice; next, ME or EM should be used, and if none of these drugs produce the desired effects, prostaglandins should be used to control bleeding. Ergot alkaloid use in gynaecology has been limited and today is discouraged even in essential menorrhagia. It is suggested that EM and ME be used (parenterally) only in first trimester abortion curettage, to reduce blood loss. Bromocriptine has been used for lactation suppression. However, alternatives such as cabergoline, which possess fewer adverse effects, are now available and therefore preferred for this indication. In sum, there is no place for the prophylactic use of ME and EM in obstetrics or gynaecology. They can be used for therapeutic purposes in the third stage of labour. During use, the practitioner must be alert for adverse effects.

The pharmacokinetics and enterohepatic cycling of oestradiol have been studied after three oral, single-dose administrations of equimolar doses of oestradiol alone, oestradiol plus desogestrel and oestradiol valerate, in a 3-way cross-over mode in 18 healthy postmenopausal women. Oestradiol was readily absorbed and metabolized to oestrone, which reached much higher serum concentrations (140pgmL(-1)) than its parent compound (35pgmL(-1)). All three formulations had the same kinetic profile and were bioequivalent on testing. Noticeable first and second absorption phases were apparent from the oestradiol and oestrone serum concentration-time curves for all oestradiol formulations. The mean serum concentration-time curves of the metabolite oestrone (corrected for endogenous oestrone) showed a second maximum at approximately 25h. By means of line feathering, serum concentration-time curves were constructed which belonged to the first, second and third phases of absorption. The maximum serum concentration, Cmax, of the second absorption or recirculation of oestrone was 20% that of the first, and the Cmax of the third circulation was 50% that of the second. The areas under the serum-concentration-time curves (AUC) for the second and third recirculations were similar-each comprised 12-13% of the total AUC. The oral clearance values of the recirculations were constant (590Lh(-1)). Enterohepatic recirculation of endogenous compounds is aimed at maintaining a steady-state serum concentration for immediate use and hydrolysis in the target organs. It is concluded that exogenously added oestradiol and its metabolites follow the recirculation pathways of the endogenous oestrogen pool.

The aim of this investigation was to assess the effects and disposition kinetics of the local anaesthetic drugs (+/-) articaine and lidocaine during intravenous regional anaesthesia (IVRA). The mean onset time of surgical analgesia of articaine was 2.5 +/- 1.1 min and that of lidocaine 11.2 +/- 5.1 min (p = 0.0006). None of the patients exhibited objective symptoms of toxicity, either local or systemic, during injection of articaine or lidocaine, nor were there any subjective complaints. No changes in blood pressure, heart rate or oxygen saturation were observed with these local anesthetics at any time during the procedure, nor after deflation of the tourniquet. After releasing the tourniquet, articaine appears in the blood and is rapidly eliminated with a t1/2 alpha of 5 +/- 3 min and a t1/2 beta of 59 +/- 39 min due to hydrolysis. Lidocaine is rapidly and biexponentially eliminated with similar half-lives of t1/2 alpha of 4 +/- 2 min and a t1/2 beta of 79 +/- 31 min. Total body clearance of articaine (8.9 +/- 3.5 L/min) is ten times greater than that of lidocaine (0.9 +/- 0.4 L/min; p = 0.0005). We concluded that both (+/-) articaine and lidocaine are suitable and safe agents for IVRA with rapid onset of good surgical anaesthesia. Articaine is a racemic mixture, which is nowadays considered as less favourable. After releasing the tourniquet, articaine is eliminated with a t1/2 beta of 60 min and lidocaine with a t1/2 beta of 80 min. Quicker onset and shorter elimination time favours (+/-) articaine over lidocaine for IVRA in day case settings so that patients treated with articaine will be 'drug free' more quickly than those who receive lidocaine. Faster elimination and more rapid onset are important advantages for articaine in IVRA for day-case procedures.

An end-stage renal failure patient, receiving chronic treatment with the anticonvulsants, sodium valproate and primidone, showed accelerated recovery with enhanced elimination (T1/2(z) = 52 min) and clearance (Cl = 14.4 ml min-1 kg-1) of rocuronium. The pharmacokinetic and pharmacodynamic effects of rocuronium in this patient are compared with those published for healthy and renal failure patients. Increased hepatic binding of rocuronium rather than metabolism is suggested as the possible cause of this effect.

Lignocaine is a suitable and safe agent for intravenous regional anaesthesia (IVRA) with rapid onset of good surgical anaesthesia. The onset time of the local anaesthetic action of lignocaine was 11.2 +/- 5.1 min. Satisfactory surgical conditions, evidenced by good sensory blockade were achieved within 20 min, and no additional analgesics were required. There was no trend towards a fixed sequence, radial, median and ulnar in the development of sensory blockade. No patient exhibited objective symptoms of toxicity, either local or systemic, after release of the tourniquet, nor were there any subjective complaints. No changes in blood pressure, heart rate or oxygen saturation were observed at any time during the procedure, or after deflation of the tourniquet. After releasing the tourniquet lignocaine is rapidly and biexponentially eliminated, with a t1/2a of 4.3 +/- 2.1 min and a t1/2 beta of 79.1 +/- 31.2 min. Total body clearance was 0.86 +/- 0.39 L min-1. Eight patients showed rapid release of lignocaine from the exsanguinated area. In two patients the systemic plasma concentration of lignocaine increased more slowly than in the remaining eight. This can be explained by a greater degree of lignocaine absorbtion in the tissues of the arm. Pharmacokinetic constants after rapid and slow absorption were calculated.

Objective: The aim of this investigation was to compare the clinical effects and pharmacokinetics of lidocaine and prilocaine in two groups of 15 patients undergoing axillary brachial plexus anaesthesia., Methods: The study had a randomised design. Patients were allocated to one of the two groups of 15. Each group received either lidocaine (600mg = 2.56 mmol/L + 5 mg/L adrenaline) or prilocaine (600mg = 2.72 mmol/L + 5 mg/L adrenaline), injected over a period of 30 seconds. Onset of the surgical analgesia was defined as the period from the end of the injection of the local anaesthetic to the loss of pinprick sensation in the distribution of all three nerves., Results: The mean onset time of surgical analgesia of both lidocaine and prilocaine was 10 minutes. Lidocaine was biexponentially eliminated with a rapid elimination phase half-life (t((1/2)alpha)) of 9.95 +/- 14.3 minutes and a terminal elimination phase half-life (t((1/2)beta)) of 2.86 +/- 1.55 hours. Lidocaine was metabolised to MEGX (monoethylglycylxylidide); time to reach maximum plasma concentration (tmax) 2.3 +/- 0.8 hours; maximum plasma concentration (C(max)) 0.32 +/- 0.13 mg/L; t((1/2)beta) 2.4 +/- 2.4 hours. Lidocaine total body clearance was 67.8 +/- 28.8 L/h. Prilocaine was rapidly and biexponentially eliminated with a t((1/2)alpha) of 9.4 +/- 18.4 minutes and a t((1/2)beta) of 2.12 +/- 1.28 hours. The total body clearance of prilocaine (150 +/- 53 L/h) was higher than that of lidocaine (p = 0.0255). Both compounds demonstrated a comparable volume of distribution (Vd), while the volume of distribution at steady-state (V(ss)) and the volume of distribution in the second compartment (V(beta)) values of prilocaine were a factor of 1.6 higher than those of lidocaine (p < 0.001). Both compounds showed a comparable t((1/2)alpha) (p > 0.8) and a comparable t((1/2)beta) (p = 0.26)., Conclusion: Following axillary administration, lidocaine and prilocaine demonstrated similar pharmacokinetic behaviour and could therefore be used as the clinical preference for this regional anaesthesia technique.

Aims: To study the pharmacokinetics of articaine and its metabolite articainic acid, in patients undergoing intravenous regional anaesthesia., Methods: Ten patients (three male, seven female, ASA class 1-2), scheduled for surgery of the hand or forearm were included in the study. Articaine (40 ml, 0.5% solution (200 mg) was injected over 30 s. In total fifteen arterial blood samples were taken; one before injection and then at 10 min intervals, starting 10 min after completion of injection, until the tourniquet was released; thereafter blood samples were drawn at intervals of 1, 5, 10, 15, 20, 25, 30, 45, 60, 75 and 90 min. The tourniquet was released 30 min after completing the injection., Results: During tourniquet application and regional analgesia of 30 min duration, 55% of articaine was hydrolysed by plasma (20%) and tissue (35%) esterase activity to the metabolite articainic acid. After releasing the tourniquet, articaine and its metabolite appeared in the blood; articaine was rapidly eliminated with a t1/2z of approximately 60 min. The plasma concentration of the metabolite articainic acid was the sum of the amount formed during IVRA (55%) and the amount formed after tourniquet release (45%)., Conclusions: Articaine is a safe agent for intravenous regional anaesthesia (IVRA) with rapid onset of good surgical anaesthesia. During tourniquet application and regional analgesia, 55% of the administered dose is already hydrolysed, thus reducing the chance of side effects after tourniquet release.

The clinical pharmacokinetics, metabolism and renal excretion of articaine and its metabolite articainic acid have been investigated in man after epidural administration. (+/-)-Articaine and its metabolite (+/-)-articainic acid have different pharmacokinetic constants (P = 0.0079) except for lag-time (tlag; 0.06 min), first phase distribution of elimination (t 1/2 alpha; 0.49 +/- 0.21 h), and elimination half life (t 1/2 beta; 2.19 +/- 0.98 h), which are all the same for both compounds. The total body clearance of articaine (103 +/- 57 L h-1) is 10 times higher than that of the metabolite articainic acid (10.7 +/- 1.80 L h-1, P = 0.0079). With similar half-life (t 1/2 beta) values (2h), the volumes of distribution (V beta) are 10 times higher for the parent drug than for the metabolite ((329 +/- 212 L compared with 38.4 +/- 7.5 L, respectively; P = 0.0079). The difference between the areas under the curves for total plasma articainic acid and that formed in the plasma gives an indication of the percentage metabolism during epidural transfer (5.38 +/- 1.51%). This percentage of metabolism corresponds to a mean epidural transfer time of 5 min. The main compound in the urine is articainic acid (64.2 +/- 14.4%), followed by articainic acid glucuronide (13.4 +/- 4.97%) and the parent drug (1.45 +/- 0.77%). In total, 79.0 +/- 18.5% of the dose is recovered in the urine. The renal clearance of articaine is 22.5 +/- 13.9 mL min-1, whereas that of articainic acid is 119.6 +/- 30.1 mL min-1 (P < 0.0001). The apparent renal clearance of articainic acid glucuronide was 25.4 +/- 12.0 mL min-1. This value does not differ from that of the parent drug (P > 0.8). Articainic acid glucuronide is not present in plasma, but has an apparent renal clearance of 25 mL min-1. These results suggest that articainic acid is glucuronidated by the tubular cells and then excreted.

Background and Objectives: The purpose of this study was to compare the effectiveness of three local anesthetic agents for intravenous regional anesthesia in the upper limb. Side effects and plasma concentrations of the drugs in the doses administered for IVRA were also studied., Methods: Thirty patients in ASA groups I and II received intravenous regional anesthesia for surgery of the upper limb. In a double-blind prospective study, they were randomly allocated to receive one of three local anesthetics: articaine, lidocaine, or prilocaine. Patients received 40 mL of a 0.5% solution of the local anesthetic. The onset time of sensory block was assessed by pinprick and the extent of motor block was was scored as 0-3. Plasma concentrations of local anesthetics were determined in all patients from serial arterial blood samples drawn at predetermined times before and after tourniquet release., Results: The onset time of sensory block was significantly shorter (2.5 minutes) in the articaine group than in the lidocaine group (11.1 minutes) or the prilocaine group (10.9 minutes) (Scheffe, P < .05). Development of motor block was equal in all three groups (score 2). Estimation of plasma concentrations by high performance liquid chromatography showed that the peak level in all 30 patients was reached immediately after release of the tourniquet; plasma concentrations thereafter gradually declined. Maximum concentrations of articaine, lidocaine, and prilocaine were, 1.85, 8.5, and 4.4 micrograms/mL, respectively. No signs of local anesthetic toxicity of the cardiovascular or central nervous systems were seen., Conclusion: Articaine had the fastest onset of sensory block and the lowest peak plasma concentration of the three local anesthetics when used for intravenous regional anesthesia.

1. The influence of sulphasalazine (SASP) on the pharmacokinetics of low dose methotrexate (MTX) and the relation between pharmacokinetic variables and clinical response was studied in 15 patients with active rheumatoid arthritis despite > 6 months of SASP treatment. 2. SASP was stopped for 2 weeks. Thereafter a single oral dose of 7.5 mg MTX was administered after a standard breakfast. Blood was sampled initially every 30 min, thereafter hourly during 8 h. Urine was sampled every hour. Then 2000 mg SASP daily + 7.5 mg MTX weekly was given. After 4 weeks the same procedure was repeated supplemented with concomitant administration of 1000 mg SASP. Clinical measurements included Ritchie articular index, number of swollen joints, ESR and the disease activity score. Pharmacokinetic analysis was performed using a two-compartment model with first order absorption and lag time. Results are given as mean (s.d.). Paired t-test or signed rank test were applied in the statistical analysis. 3. Pharmacokinetics of MTX without vs with SASP, means +/- s.d. were follows: AUC: 673 +/- 179 vs 628 +/- 210 (95% confidence interval [CI] of the difference was -71 to 159) ng ml-1, MRT: 5.2 +/- 1.3 vs 5.2 +/- 1.1 (95% CI -0.4 to 0.4) h, t1/2,z: 4.3 +/- 1.1 vs 4.2 +/- 1.1 (95% CI -0.3 to 0.5) h, V/F: 59.3 +/- 29.3 vs 65.5 +/- 25.3 (95% -23.8 to 11.4) 1, CL/F: 12.3 +/- 5.0 vs 13.5 +/- 4.8 (95% CI -4.5 to 2.3) 1 h-1. CLR/F: 6.2 +/- 1.3 vs 6.3 +/- 2.1 (95% CI -1.3 to 1.1) l h-1. All P values were > or = 0.3. 4. A weak correlation existed between the change of ESR and the MRT, the t1/2,z and the V/F (Spearman correlation coefficients of 0.43, 0.50 and 0.50 respectively, 0.05 < P < 0.1). 5. There is no significant influence of chronic SASP administration on the pharmacokinetics of MTX or vice versa. Of the clinical variables, only the ESR correlated consistently with some pharmacokinetic variables on MTX.

It is postulated that the unstable hydroxylamine metabolite of sulphamethoxazole is responsible for the adverse reactions to co-trimoxazole and in HIV infection systemic glutathione deficiency leads to a reduced capacity to counteract the hydroxylamine toxicity. This hypothesis has been investigated by studying the metabolism of sulphamethoxazole and assessing glutathione status in HIV infection in order to explore the modification of treatment. It is concluded that the toxicity of plasma sulphamethoxazole hydroxylamine is counteracted by normal glutathione concentrations as is the case in HIV-seropositive patients, but that increased oxidation within certain cells in HIV infected individuals may possibly give rise to increased concentrations of reactive intermediates of sulphamethoxazole. Sulphametrole and sulphamethoxazole have similar half-lives but are metabolized differently: in vivo no oxidised metabolites of sulphametrole could be detected. In a retrospective study the rate of adverse reactions to trimethoprim-sulphametrole appeared to be in the lower range of those reported for trimethoprim-sulphamethoxazole indicating that the combination of trimethoprim-sulphametrole may be more favourable. The ratio of trimethoprim:sulphonamide is 1:5, but in-vitro studies with Toxoplasma gondii indicate that because of the synergic effect of both agents the dose of sulphonamide is possibly unnecessarily high.

Intact and gonadectomized male and female WAG/ Rij rats were used to study the effects of gender and gonadal hormones on the development of sensitization and tolerance to cocaine-induced changes in EEG and behaviour. The four groups of WAG/Rij rats differed in the number of spontaneously occurring spike-wave discharges: ovariectomy decreased and castration increased the number of spike-wave discharges. This confirms that testosterone has antiabsence effects and that female gonadal hormones may promote the occurrence of spike-wave discharges. Cocaine [10 and 20 mg/kg, intraperitoneally (IP)] was administered before and after chronic cocaine administration (9 days, one daily injection with 10 mg/kg) and EEG and behaviour were monitored. Cocaine strongly suppressed the occurrence of spike-wave discharges before and after chronic administration in all four groups, although the decrease was less in the intact males. Sensitization or tolerance induced by cocaine on EEG could not be established. Acute cocaine administration eliminated explorative, automatic, and passive behaviour, whereas various stereotypical activities such as uncoordinated head and body movements and head swaying emerged. Differences between groups were observed as intact males were less likely than subjects in the three other groups to engage in intense stereotyped behaviour. These data suggest that testosterone inhibits EEG and behavioural effects of acute cocaine administration. All four groups displayed less head swaying and more uncoordinated head and body movements after chronic cocaine administration, suggesting that behavioural sensitization had occurred. Differences between the four groups had faded away. Although pharmacokinetic differences in levels of cocaine and benzoylecgonine between the four groups were found, they could not easily be related to the behavioural differences between groups.

The pharmacokinetics of 80 mg frusemide given orally were investigated in normal subjects using a direct HPLC method for parent drug and its acyl glucuronide conjugate. Two half-lives could be distinguished in the plasma elimination of both frusemide and its conjugate, with values of 1.25 +/- 0.75 and 30.4 +/- 11.5 h for frusemide and 1.31 +/- 0.60 and 33.2 +/- 28.0 h for the conjugate. The renal excretion rate-time profile showed two phases; the rapid elimination phase lasted from 0-15 h and the second and slow phase, from 15-96 h. During the first 15 h, 33.3 +/- 4.8% of the dosed frusemide was excreted; in the remaining period 15-96 h, 4.6 +/- 1.5% was excreted. In the same two periods the excretion of the glucuronide was 13.4 +/- 4.7 and 1.9 +/- 1.1%, respectively. The mean renal clearance of frusemide was 90.2 +/- 16.9 mL min-1 during the first period and 91.5 +/- 29.3 mL min-1 in the remaining period, during which the stimulation of urine production was absent. The renal clearance of the acyl glucuronide was 702 +/- 221 mL min-1 in the first period, but only 109 +/- 51.0 mL min-1 in the second period. The stimulated urine production in the first 6 h after administration amounted to 2260 +/- 755 mL (measured urine production minus baseline value of 1 mL min-1 (360 mL). During the second or rebound period (6-96 h after drug administration), the quantity of urine was 990 +/- 294 mL lower than what would have been expected from the baseline production of 5400 mL. This reduced production (0.82 mL min-1) is equivalent to an 18% reduction in the average urine flow rate of 1 mL min-1.

The following metabolites of sulfadiazine (S) were isolated from monkey urine by preparative HPLC: 5-hydroxysulfadiazine (5OH), 4-hydroxysulfadiazine (4OH) and the glucuronide (5OHgluc) and sulfate conjugate of 5OH (5OHsulf). The compounds were identified by NMR, mass and infrared spectrometry and hydrolysis by beta-glucuronidase. The analysis of S, the hydroxymetabolites (4OH, 5OH) and conjugates N4-acetylsulfadiazine (N4), 5OHgluc and 5OHsulf in human and monkey plasma and urine samples was performed using reversed-phase gradient HPLC with UV detection. In plasma, S and N4 could be detected in high concentrations, whereas the other metabolites were present in only minute concentrations. In urine, S, the metabolites and conjugates were present. The limit of quantification of the compounds in plasma varies between 0.2 and 0.6 microgram/ml (S 0.31, N4 0.40, 4OH 0.20, 5OH 0.37, 5OHgluc 0.33 and 5OHsulf 0.57 microgram/ml). In urine it varies between 0.6 and 1.1 micrograms/ml (S 0.75, N4 0.80, 4OH 0.60, 5OH 0.80, 5OHgluc 0.80 and 5OHsulf 1.1 micrograms/ml). The method was applied to studies with healthy human subjects and Rhesus monkeys. The metabolites 5OH, 5OHgluc and 5OHsulf were present in Rhesus monkey and not in man. Preliminary results of studies of metabolism and pharmacokinetics in Rhesus monkey and man are presented.

The kinetics of 20 mg nicomorphine intramuscularly were described in 8 patients under combined general and epidural anesthesia. The half-life of nicomorphine was 0.32 +/- 0.20 h (mean +/- SD) and is governed by the absorption-rather than the elimination rate. The half-life of 6-mononicotinoylmorphine (0.39 +/- 0.09 h) was identical to that of the parent compound (p = 0.29), suggesting it is directly related to the absorption rate of nicomorphine. Morphine had a half-life of 1.38 +/- 0.31 h. Morphine is subsequently metabolized into morphine-3-glucuronide and morphine-6-glucuronide. The half-life of these 2 glucuronide conjugates was about 2.6 h (p = 0.07). A glucuronide conjugate of 6-mononicotinoylmorphine was not detected. In urine only morphine and its glucuronides are found, with renal clearance values of 214 ml.min-1 for morphine and 132 ml.min-1 for the glucuronides. The bioavailability of this pharmaceutical formulation after intramuscular administration equals that of intravenous administration in surgical patients (at the same dose).

After epidural administration of 15 mg 3, 6-dinicotinoylmorphine (nicomorphine) in 10 patients undergoing pulmonary surgery, the parent compound was quickly metabolized into the metabolites 6-mononicotinoylmorphine and morphine. The mean apparent half-lives (+/- SD) of elimination were 10 min (0.165 h +/- 0.053 h) for 3,6-dinicotinoylmorphine and 1.77 h +/- 1.23 h for 6-mononicotinoylmorphine. Morphine is subsequently metabolized into morphine-3-glucuronide and morphine-6-glucuronide. The apparent half-lives of morphine, morphine-3-glucuronide, and morphine-6-glucuronide are similar: 3.63 h +/- 1.63 h, 4.10 h +/- 0.57 h, and 4.20 h +/- 1.64 h respectively. The possible glucuronide conjugate of 6-mononicotinoylmorphine was not detected. The prodrug 3,6-dinicotinoylmorphine was biotransformed into three active compounds: 6-mononicotinoylmorphine, morphine, and morphine-6-glucuronide.

The aim of this investigation was to assess the bioavailability and pharmacokinetics of oxytocin in six male subjects after a sublingual dose of 400 int. units (684 micrograms) and after an intravenous dose of 1 int. unit (1.71 micrograms). After intravenous administration, the pharmacokinetic profile could be described with a two-compartment model. The distribution half-life was 0.049 +/- 0.106 h, the elimination half-life was 0.33 +/- 0.23 h, the total body clearance was 67.1 +/- 13.4 L h-1 and the volume of distribution was 33.2 +/- 28.1 L. After sublingual administration, a poor bioavailability with a 10-fold variation between 0.007 and 0.07% was observed. The pharmacokinetic profile could be described with a one-compartment model. The lag time was subject-dependent and ranged between 0.12 and 0.30 h (40% CV). The absorption half-life was 0.45 +/- 0.29 h, and the apparent elimination half-life 0.69 +/ - 0.26 h. This study showed a very poor and interindividual variability in bioavailability. The sublingual route of administration with its 'long' lag time and 'long' absorption half-life would not seem a reliable route for accurate high dosing for immediate prevention of post-partum haemorrhage.

Objective: To study the pharmacodynamic and pharmacokinetic properties of oral and intravenous methylergometrine upon uterine motility during menstruation., Study-Design: Intra-uterine pressure was measured in six volunteers with a fluid-filled sponge-tipped catheter during menstruation. Methylergometrine was given orally (0.5 mg) or intravenously (0.2 mg) in a cross-over design., Results: After intravenous administration, a fast increase of the frequency of uterine contractions and basal tone occurred with a decrease of amplitude, lasting at least 30 min. Oral administration had a late and less marked effect on uterine motility. An intravenous dose administered 24 h after an oral dose had no effect on uterine motility. Pharmacokinetic data, such as the maximum plasma concentration (Cmax), the time at which Cmax is reached (tmax) and the half-life of absorption (t1/2abs) also demonstrated large individual variations after oral administration., Conclusions: Oral administration of methylergometrine had an unpredictable and late effect on uterine motility on the menstruating uterus, probably due to an unpredictable bioavailability, in contrast with the fast and predictable effect after intravenous administration.

1. The urinary excretion of sulphamethoxazole and its metabolites was compared between healthy volunteers and HIV-seropositive patients in order to get a better understanding of why HIV seropositives are more predisposed to idiosyncratic toxicity of sulphonamides. 2. A single 800 mg oral dose of sulphamethoxazole was administered to seven healthy volunteers and seven asymptomatic HIV seropositives without previous use of sulphonamides. 3. Urine was collected for 4 days and drug analysis was by h.p.l.c. 4. No difference was observed between seropositive and seronegative individuals in the urinary recovery of sulphamethoxazole, N4-acetyl-, 5-hydroxy-, N4-acetyl-5-hydroxy-sulphamethoxazole and the N1-glucuronide conjugate. However the recovery of the hydroxylamine metabolite of sulphamethoxazole was significantly lower in the HIV seropositives (0.50 +/- 0.51 vs 2.23 +/- 0.85%; 95% CI on the difference, -0.90 to -2.55; P = 0.0006). 5. Sulphamethoxazole hydroxylamine may be a factor in the susceptibility of HIV infected individuals to sulphonamides.

The effect of oral probenecid (1 g) on the pharmacokinetics of frusemide (80 mg p.o.) and its acyl glucuronide was studied in nine healthy subjects. Probenecid significantly increased the t1/2,z of frusemide from 2.01 +/- 0.68 to 3.40 +/- 1.48 h (P = 0.0015) and significantly decreased oral clearance from 164 +/- 67.0 to 58.3 +/- 28.1 ml min-1 (P = 0.0001). No effect of probenecid on the plasma protein binding of frusemide was detected. Probenecid significantly increased the tmax of the metabolite frusemide acyl glucuronide from 1.4 to 2.6 h, but had no effect on the tlag, Cmax, t1/2,z and plasma protein binding. The urinary recoveries of unchanged frusemide (39.2 +/- 10.2 vs 34.4 +/- 8.6%, P = 0.28) and its acyl glucuronide (12.1 +/- 2.7 vs 11.8 +/- 3.7%, P > 0.8) were not altered by probenecid. However, probenecid decreased the renal clearance of both frusemide (128 +/- 49 vs 44.0 +/- 18.6 ml min-1, P = 0.0002) and the acyl glucuronide (552 +/- 298 vs 158 +/- 94.0 ml min-1, P < 0.0001). The non-renal clearance of frusemide (36.7 +/- 21.0 vs 15.2 +/- 13.4 ml min-1, P = 0.0068) was also decreased. The clinical relevance of the study relates to the possible conjugation of frusemide in the kidney and the role of the conjugate in the pharmacodynamic effect.

Objective: To assess and compare the pharmacokinetics and bioavailability of methylergometrine (ME) in men and non-pregnant women., Design: A cross-over design was used for an oral dose of 0.125 mg and an intravenous dose of 0.200 mg of ME in 6 men and 6 non-pregnant women (parallel-design in gender)., Results: After intravenous administration, the pharmacokinetic profile of ME was described with a 2-compartment model. The distribution half-life (t1/2 alpha) in men was 0.19 +/- 0.27 h, in women 0.10 +/- 0.04 h, the elimination half-life (t1/2 beta) 1.85 +/- 0.28 h, respectively, 1.94 +/- 0.34 h and the total body clearance (CL) 33.2 +/- 11.8 l.h-1, and, respectively, 22.18 +/- 3.10 l.h-1. For these intrinsic pharmacokinetic parameters differences between men and women were not statistically significant. After oral administration, the pharmacokinetic profile was described with a 1-compartment model. The lag time was subject dependent and was significantly longer in men 0.33 +/- 0.09 h than in women 0.09 +/- 0.07 h. T1/2 beta in men was 2.08 +/- 0.43 h and was longer than in women 1.42 +/- 0.31 h (p = 0.012). In both men and women a large variation of bioavailability was shown ranging between 22% and 138%., Conclusion: This study with oral methylergometrine showed a comparable large interindividual variability in bioavailability in both men and women.

Objectives: This study is part of a programme on reduction of postpartum haemorrhage (PPH). Ergometrine and methylergometrine have a favourable effect on both blood loss and maternal morbidity and mortality and oral preparations were regarded as a possible treatment for use in tropical countries. The stability of oral preparations of the two ergometrine compounds under tropical conditions was unknown and was therefore examined in this study., Study Methods: The 'experimental shelf lives' of ergometrine and methylergometrine tablets were examined by exposing the tablets to seven artificially controlled conditions. Samples were analysed by high performance liquid chromatography at nine different sampling times over a period of 1 year to determine the content of ergometrine and methylergometrine., Results: Under refrigeration (test I), less than 90% of the stated amount of active ingredient was found in the tablets after 14 weeks in the case of ergometrine and 21 weeks in the case of methylergometrine. When stored in the dark at 40 degrees C and 75% relative humidity (test VI), the tablets fall outside accepted specification (= 90-110% of state amount of active ingredient) within 3 weeks in the case of ergometrine and 21 weeks in the case of coated methylergometrine tablets. The stability of uncoated ergometrine tablets was far less than that of coated methylergometrine tablets. Instability worsened under extreme humid conditions (test IV and VI), and hot conditions (test V), for both ergometrine and methylergometrine. From week 31 onwards the coating did not seem to protect the compound anymore, irrespective of the condition of exposure., Conclusions: Tropical conditions make the tablets unstable with humidity as the main adverse factor. The sugar-coated methylergometrine tablets are more stable under humid/hot conditions than the non-coated ergometrine tablets. Under all simulated conditions both oral ergometrine and methylergometrine tablets are unstable.