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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.

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.

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.

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 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.

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 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.

To investigate whether dogs are able to excrete acetylated drugs by active transport, the plasma kinetics and renal excretion of the N4-acetyl metabolites of sulphasomidine and sulphadimethoxine were studied in the beagle dog after a rapid intravenous bolus injection. Two doses of N4-acetylsulphasomidine (1050 and 105 mg) and one dose of N4-acetylsulphadimethoxine (472 mg) were administered on separate occasions. The renal clearance (CLR) was as follows: N4-acetylsulphasomidine (1050 mg) 34 mL min-1; N4-acetylsulphasomidine (105 mg) 28 mL min-1; and N4-acetylsulphadimethoxine (472 mg) 24 mL min-1. CLR was higher than expected on the basis of the measured glomerular filtration rate, indicating that the N4-acetyl metabolites may be excreted by the renal tubules by active tubular transport. Saturation of the excretion process of N4-acetylsulphasomidine occurred with a transport maximum of 930 +/- 190 micrograms min-1 and a Michaelis-Menten constant of 37 +/- 10 micrograms mL-1. It may be concluded that the dog renal organic anion transport system is able to secrete acetylated sulphonamides.

The effect of equimolar cumulative concentrations of 11 different benzodiazepines on the indirectly evoked twitch contraction was investigated in the rat in-vitro phrenic nerve-hemidiaphragm preparation. Depending on the pattern of the concentration-response curves two groups of benzodiazepines can be distinguished: (i) a first group with a biphasic action, e.g. potentiation of twitch tension in low concentrations and depression of twitch tension in high concentrations, and (ii) a second group with primary depression of twitch tension with increasing concentrations. All of the tested compounds ultimately caused a 100% depression of twitch tension at concentrations ranging from 0.175 to 0.35 mmol litre-1. Although this peripheral effect of benzodiazepines on neuromuscular function is not the main site of action of these compounds, there are enough arguments to state that it is not a simple toxic effect. There is some evidence from this study that the peripheral component of the benzodiazepine effect on muscle relaxation may involve a multi- rather than one single receptor system.