A New Method for the Measurement of Nitrosoureas in Plasma: an H.P.L.C. Procedure for the Measurement of Fotemustine Kinetics

1. An analytical method for a novel nitrosourea, fotemustine, has been developed using solid-phase extraction and?h.p.l.c. with u.v. detection. As part of the development, different methods for stabilising fotemustine after sample collection have been investigated. The method has been successfully applied to pharmacokinetic studies in monkeys and man.

2. Providing plasma was separated immediately from blood and frozen within 3?min of collection, negligible degradation of fotemustine occurred. The samples could then be stored at —20°C in the dark for up to six days particularly if thawing prior to analysis was accelerated using a 50°C water-bath so that it was complete within 3?min. Equivalent results were also obtained with samples stabilised with 0·1?m citric acid immediately after the preparation of plasma.

3. The analytical method showed good precision with a within-day variation ranging between ±10.7% at the lowest concentration investigated (0.1 μg ml^?1) to 2.0% at 50.0 μgml^?1. The accuracy of measurement was from 108.9% to 97.6% at 0.1 and 50.0 μg ml^?1 respectively and the response was linear up to 50 μg ml^?1. The minimum level of quantitation was 20 ng ml^?1.

4. After a single intravenous bolus dose of [¹⁴C]fotemustine (100mg m^?2) to Cynomolgus monkeys, intact drug levels rapidly declined (t_1/2 12.6±0.5?min) although the halflife of radioactivity (approx 100?h) was much longer. The plasma clearance of fotemustine was 225±63 ml min^?1 with a volume of distribution based on area of 4.1±1.2 litres.

5. As with monkey, plasma levels of intact fotemustine in a patient given [¹⁴C]-drug as a 1?h constant rate intravenous infusion (approx. 100?mg m^?2), declined rapidly but with a half-life of 23.2?min. Again, the half-life for total radioactivity was considerably longer (30.8?h). The plasma clearance was 1426 ml min^?1 and the volume of distribution based on area was 47.71.     

The disposition of primaquine in the isolated perfused rat liver. Stereoselective formation of the carboxylic acid metabolite

The disposition of (+) and (-) primaquine (PQ) was studied in the isolated perfused rat liver (IPRL) preparation following a bolus dose (2.0 mg diphosphate salt; N = 6) of each enantiomer. Perfusate plasma concentrations of PQ and the carboxylic acid metabolite (PQm) were determined using previously reported methods. To enable the simultaneous measurement of PQ and PQm in bile a selective and reproducible HPLC assay was developed. Clearance of (-)PQ (8.8 +/- 2.9 ml min-1) was significantly greater than that of (+)PQ (5.5 +/- 1.5 ml min-1) and the apparent volumes of distribution of (-)PQ (606 +/- 182 ml) and (+)PQ (930 +/- 171 ml) were significantly different. Stereoselectivity in the hepatic elimination efficiency was manifest as a significant reduction in half-life (-)PQ 54 +/- 29 min; (+)PQ 123 +/- 33 min) and smaller area under the curve to infinity (-)PQ 254 +/- 96 micrograms ml-1.min, (+)PQ 387 +/- 108 micrograms ml-1.min) for (-)PQ when compared with (+)PQ. A significantly greater peak concentration of PQm was achieved following administration of (-)PQ (0.61 +/- 0.26 micrograms ml-1.min) than (+)PQ (0.19 +/- 0.09 micrograms ml-1). There was no difference between the sum of the areas under the curve to 4 hr for (+) and (-)PQ and the corresponding carboxylic acid metabolite (322 +/- 64 micrograms ml-1 and 317 +/- 75 micrograms ml min-1 respectively). There was no difference in the biliary clearance of (+) and (-)PQ (0.08 +/- 0.02 ml min-1 and 0.14 +/- 0.10 ml min-1 respectively) or the corresponding carboxylic acid metabolites (0.24 +/- 0.13 ml min-1 and 0.29 +/- 0.09 ml min-1). These results strongly suggest stereoselective formation of the carboxylic acid metabolite of primaquine. The significant increase in the volume of distribution of (+)PQ suggests the enantiomer has either an increased affinity for binding sites within the liver and/or erythrocytes or a decreased affinity for circulating perfusate albumin.     

Metabolism and pharmacokinetics of 14C-pentoxifylline in healthy volunteers

The metabolism and pharmacokinetics of 14C-pentoxifylline (Trental) have been studied in three healthy male volunteers after oral administration of 200 mg (50 microCi). The radiolabelled drug was rapidly absorbed and by 6 h 89.1 +/- 2.4% of the 14C material was excreted in the urine. The dosed 14C material (96.9 +/- 2.2%) was recovered in excreta by 24 h with 93.3 +/- 2.3% in the urine 3.0 +/- 0.2% in the faeces. Peak plasma levels of radioactivity (4.1-6.2 micrograms eq ml-1) occurred 0.25-0.75 h after administration. This radioactivity decayed in a biexponential fashion with an initial half-life of 1.01 +/- 0.13 h and a terminal half-life of 36.06 +/- 16.94 h. The peak plasma levels (0.48-2.25 micrograms ml-1) of parent drug, as measured using a specific gas chromatographic assay also occurred at 0.25-0.75 h and subsequently decayed extremely rapidly with an initial half-life of 0.18 +/- 0.15 h and terminal half-life of 0.76 +/- 0.44 h. Urinary 14C-labelled metabolites were separated by semi-preparative high performance liquid chromatography and characterised by mass spectrometry and by comparison with authentic synthetic compounds. Of the dosed 14C-pentoxifylline, greater than 90% could be identified as characterised metabolites in urine.     

The role of CYP2D6 in primary and secondary oxidative metabolism of dextromethorphan: in vitro studies using human liver microsomes.

1. The pharmacokinetics of [R]-leucovorin ([R]-LV), [S]-leucovorin ([S]-LV) and the circulating metabolite [S]-5-methyltetrahydrofolate ([S]-5-MTHF) were studied after administration of racemic LV and [S]-LV in 21 subjects. 2. After intravenous infusion of 600 mg m-2 rac-LV (group 1, n = 7) or 300 mg m-2 [S]-LV (group 3, n = 7), the decay of [S]-LV in plasma was biexponential with a distribution half-life of 0.8 to 1 h and an elimination half-life of 11 to 23 h. When rac-LV was administered as a 2 h i.v. infusion (400 mg m-2) following a loading dose of 200 mg m-2 (group 2, n = 7), the plasma concentrations of [R]-LV and [S]-5-MTHF decayed monoexponentially with mean (+/- s.d.) half-lives of 10 +/- 3 h and 7 +/- 2 h, respectively. 3. The AUC of [S]-5-MTHF was significantly higher after infusion of 300 mg m-2 [S]-LV than after infusion of 600 mg m-2 rac-LV (83 +/- 22 micrograms ml-1 h vs 53 +/- 22 micrograms ml-1 h; P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of diflunisal on the pharmacokinetics of oxazepam.

Single dose pharmacokinetics of oxazepam, 30 mg, have been studied in six healthy male volunteers in the absence of diflunisal and during continuous treatment with diflunisal 500 mg twice daily. During diflunisal treatment, peak plasma concentration of oxazepam significantly decreased from 387 +/- 18 ng ml-1 (mean +/- s.e. mean) to 241 +/- 10 ng ml-1 and total area under the plasma concentration-time curve (AUC) significantly decreased from 5536 +/- 819 ng ml-1 h to 4643 +/- 562 ng ml-1 h. The AUC of oxazepam glucuronide significantly increased from 4771 +/- 227 ng ml-1 h to 8116 +/- 644 ng ml-1 h and its elimination half-life increased from 10.0 +/- 0.6 h to 13.0 +/- 1.0 h. Renal clearance for oxazepam glucuronide was significantly reduced from 74 +/- 2 ml min-1 to 46 +/- 3 ml min-1. In vitro, diflunisal, at concentrations of 125 to 1000 micrograms ml-1, significantly displaced oxazepam from its plasma protein binding, the free fraction of oxazepam increasing by 28 to 56%. The free fraction of oxazepam glucuronide, ex vivo, increased by 49 +/- 5% (n = 3) during concomitant diflunisal treatment. These data suggest that the observed interaction between oxazepam and diflunisal results from a presystemic displacement of oxazepam from its plasma protein binding sites by diflunisal and from an inhibition of the tubular secretion of oxazepam glucuronide by the glucuronides of diflunisal.     

The effect of pirenzepine on gastric emptying and salivary flow rate: constraints on the use of saliva paracetamol concentrations for the determination of paracetamol pharmacokinetics.

1. The effects of pirenzepine on gastric emptying, salivary flow and saliva paracetamol concentrations were investigated in healthy volunteers. 2. Pirenzepine significantly reduced the area under the saliva flow-time curves (7.29 +/- 3.30 g min-1 h without pirenzepine; 4.19 +/- 2.59 g min-1 h with pirenzepine, P less than 0.01). Pirenzepine had no significant effect on plasma paracetamol Cmax (17.5 +/- 7.8 micrograms ml-1 without pirenzepine; 12.6 +/- 7.7 micrograms ml-1 with pirenzepine), plasma tmax (0.2 h (0.2-0.8 h) without pirenzepine; (0.2 h 0.2-0.8 h) with pirenzepine) and plasma AUC(0.6 h) (32.3 +/- 7.2 micrograms ml-1 h without pirenzepine; 30.3 +/- 6.5 micrograms ml-1 h with pirenzepine). 3. Mean ratios of saliva:plasma paracetamol AUC (1.06 +/- 0.24 without pirenzepine; 1.84 +/- 0.48 with pirenzepine, P less than 0.001) and saliva:plasma paracetamol Cmax (1.7 +/- 1.0 without pirenzepine; 6.5 +/- 2.7 with pirenzepine, P less than 0.01) were significantly increased by pirenzepine pretreatment, but there was a poor correlation between the percentage change in the area under the saliva flow-time curve and the percentage change in saliva paracetamol AUC (r = 0.47, P = 0.21). 4. The findings suggest that a) pirenzepine is a more selective antagonist of the muscarinic receptors in salivary glands than those in gastric smooth muscle and b) caution is required when using saliva paracetamol concentrations to determine the pharmacokinetics of the drug in the presence of other agents which may influence salivary flow rate.     

Disposition of HI-6 oxime in rats after intravenous and intramuscular administration

The pharmacokinetics of HI-6, a cholinesterase-reactivating oxime, were studied in rats, following intravenous or intramuscular administration. A two-compartment model was used to analyse the intravenous data and a one-compartment open model with first-order absorption was used for intramuscular data. Drug concentration had no influence on rate and extent of absorption of intramuscular injections, and bioavailability was 100%. Peak plasma concentrations of HI-6 occurred 15 min after intramuscular injection. No significant differences were found between mean values for half-life, plasma clearance, volume of distribution and area under the plasma concentration versus time curve for the two intramuscular doses and the intravenous dose used. Mean HI-6 plasma concentrations were 140.5 +/- 4.2 micrograms ml-1 3 min after 20 mg ml-1 i.v., with a mean elimination half-life of 65.2 +/- 21 min. Plasma clearance rate was 3.95 +/- 0.93 ml min-1 kg and the apparent volume of distribution was 0.38 +/- 0.17 litre kg-1. The oxime is rapidly distributed in and eliminated by rats when administered intravenously or intramuscularly.     

The disposition of primaquine in the isolated perfused rat liver. Effect of dose size

The disposition of 14C-radiolabeled primaquine in the isolated perfused rat liver preparation was investigated after the administration of 0.5-, 1.5-, and 5.0-mg doses of the drug. The pharmacokinetics of primaquine in this experimental model were dependent on dose size. Increasing the dose from 0.5 to 5.0 mg produced a significant reduction in clearance from 11.6 +/- 2.5 to 2.9 +/- 1.0 ml X min-1. This decrease was accompanied by a disproportionate increase in the value of AUC from 25.4 +/- 5.9 to 1128.6 +/- 575.7 micrograms X min X ml-1, elimination half-life from 33.2 +/- 10.7 to 413.0 +/- 239.3 min, and volume of distribution from 547.7 +/- 153.1 to 1489.0 +/- 249.0 ml. Furthermore, primaquine exhibited dose dependency in its pattern of metabolism. While the carboxylic acid derivative of primaquine was not detected in perfusate after the 0.5-mg dose, it was the principal perfusate metabolite after the 5.0-mg dose. Primaquine was subject to extensive biliary excretion at all doses; the total amount of 14C radioactivity excreted in the bile decreased from 60 to 30% as the dose of primaquine was increased from 0.5 to 5.0 mg. The metabolite composition of radioactivity excreted in the bile was also examined. Total recovery of the administered radioactivity from bile, perfusate, and liver was essentially complete at all doses. The perfusate concentrations at the conclusion of each experiment (i.e. 5 hr) did not differ among dosage groups. By contrast, increased dose size produced a reduction in the amount of 14C radioactivity recovered in bile which was associated with increased levels of 14C in the liver.     

The nasal absorption of sodium cromoglycate in the albino rat

The intranasal absorption of sodium cromoglycate has been investigated in the adult male COBS/Wistar rat. Sodium cromoglycate (1 mg kg-1) was instilled into the nasal cavities and for comparison animals were also similarly dosed intravenously or sub-lingually. Serial samples of blood or bile were collected. After intravenous administration, the area under the plasma concentration curve (AUC0-infinity) was 32 micrograms min ml-1 corresponding to a plasma clearance of 13 ml min-1 and an elimination rate constant of 0.049 min-1. Plasma concentrations of radioactivity after intranasal administration rose to a mean peak of 0.3 micrograms ml-1 approximately 20 min after dosing and fell to 0.03 micrograms min ml-1 at 3 h. The AUC0-3 was 19 micrograms min ml-1 corresponding to an absorption of 60% over 3 h. The absorption rate constant (ka) was 0.059 min-1. The total amount of sodium cromoglycate excreted in bile after intravenous administration was 56%. The amount of compound excreted in the bile was 30% after intranasal administration corresponding to an absorption of 53%. Plasma and bile data therefore show good agreement. Total excretion in the bile over 3 h after sub-lingual administration was 3%, demonstrating that this route made no significant contribution to the intranasal results. The absorption of sodium cromoglycate is independent of variations in the technique including changes in the orientation of the rat or blocking of the nasopalatine. The techniques used minimized other competing nasal clearance processes such as mucociliary clearance.     

The influence of cimetidine on the pharmacokinetics of 5-fluorouracil.

The influence of cimetidine pretreatment on the pharmacokinetics of 5-fluorouracil (5FU) has been studied in 15 ambulant patients with carcinoma. Neither pretreatment with a single dose of cimetidine (400 mg) nor with daily treatment at 1000 mg for 1 week altered 5FU pharmacokinetics. Pretreatment with cimetidine for 4 weeks (1000 mg daily) led to increased peak plasma concentrations of 5FU and also area under the plasma concentration-time curve (AUC). The peak plasma concentration after oral 5FU was increased by 74% from 18.7 +/- 4.5 micrograms/ml (mean +/- s.e. mean) to 32.6 +/- 4.4 micrograms/ml (P less than 0.05) and AUC was increased by 72% from 528 +/- 133 micrograms/ml-1 min (mean +/- s.e. mean) to 911 +/- 152 micrograms ml-1 min (P less than 0.05). After intravenous 5FU, AUC was increased by 27% from 977 +/- 96 micrograms ml-1 min (mean +/- s.e. mean) to 1353 +/- 124 micrograms ml-1 min (P less than 0.01). Total body clearance for 5FU following intravenous administration was decreased by 28% from 987 +/- 116 ml/min (mean +/- s.e. mean) to 711 +/- 87 ml/min (P less than 0.01). The elimination half-life of 5FU was not altered by cimetidine. The basis of the interaction between 5FU and cimetidine is uncertain but probably a combination of inhibited drug metabolism and reduced liver blood flow. The therapeutic implications are considerable and additional care should be taken in patients receiving the two drugs concomitantly.     

Dose-dependent pharmacokinetics of zoxazolamine in the rat

Zoxazolamine (ZX) is a model substrate frequently used in studies on (methylcholanthrene-inducible) hepatic cytochrome P-450 activity. The iv pharmacokinetics of ZX were studied in rats at four dose levels: 5 mg X kg-1 (n = 6), 25 mg X kg-1 (n = 6), 50 mg X kg-1 (n = 5), and 60 mg X kg-1 (n = 4). Concentrations of ZX in blood, as well as the urinary excretion of unchanged ZX and chlorzoxazone, were determined. The apparent systemic clearance (CLs,app) decreased with increasing dose from 52.6 +/- 3.9 at 5 mg X kg-1 to 9.3 +/- 0.4 ml X min-1 X kg-1 at 60 mg X kg-1. The apparent elimination half-life, t1/2,app, increased from 16.1 +/- 0.3 min to 141 +/- 28.5 min. There was only slight concentration dependency of plasma protein binding: 86.0 +/- 0.9% at 4.2 +/- 0.2 micrograms X ml-1 (n = 6) vs. 80.4 +/- 0.4% at 27.1 +/- 1.1 micrograms X ml-1 (n = 6). Since from clearance and protein binding data nonrestrictive clearance of ZX could be inferred, this small change in binding was regarded as irrelevant for the interpretation of pharmacokinetic data of ZX. The blood-plasma concentration ratio was larger than unity: 2.11 +/- 0.09 at 5.4 +/- 0.9 micrograms X ml-1, and 1.85 +/- 0.08 at 47.9 +/- 4.9 micrograms X ml-1 (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)     

Nifedipine kinetics in the rat and relationship between its serum concentrations and uterine and cardiovascular effects.

1. The kinetics of nifedipine and the relationship between its serum concentration and uterine and cardiovascular effects were investigated in 3 groups of animals. These were ovariectomized (ovx) anaesthetized non-pregnant rats following bolus i.v. injection (400 micrograms kg-1) and during 300 min infusion (10 micrograms kg-1 min-1) and ovx, progesterone-treated late pregnant rats during infusion. Also, the kinetics were determined in ovary-intact late pregnant rats following bolus i.v. injection (400 micrograms kg-1). 2. Measurement of serum nifedipine concentrations after bolus i.v. injection in ovx non-pregnant rats showed a biexponential decay with time from which the following parameters were calculated: V beta = 300 +/- 30 ml kg-1; rate constants k12 = 0.51 +/- 0.18 min-1; k21 = 0.07 +/- 0.02 min-1; ke1 = 0.10 +/- 0.05 min-1; elimination clearance = 2.4 +/- 0.2 (ml min-1) kg-1; t1/2 alpha = 2.5 +/- 1.0 min; t1/2 beta = 102 +/- 15 min. In intact pregnant rats, a biexponential decay of serum nifedipine concentrations with time was also observed after bolus i.v. administration with similar parameters to non-pregnant animals. These kinetic parameters, used to calculate serum nifedipine concentrations obtained during infusion, predicted values similar to experimental values for 180 min, but thereafter slightly underestimated experimental values. 3. Immediate reductions in uterine contractions, mean blood pressure and heart rate were observed following bolus i.v. injection of nifedipine to ovx non-pregnant rats, with returns towards control values as serum nifedipine concentrations declined. IC15 values (15% change from baseline), calculated from log10 serum concentration-response curves, of 0.3 +/- 0.05 micrograms ml-1 for inhibition of uterine contractions, 0.8 +/- 0.3 micrograms ml-1 for depression of blood pressure and 3.8 +/- 1.0 micrograms ml-1 for reduction in heart rate were obtained. 4. In ovx non-pregnant rats, nifedipine infusion produced a maximum reduction in integral of uterine contractions of 70% by 120 min and a maximum reduction of 15% in heart rate. Mean blood pressure was not significantly different from vehicle-treated rats. IC15 values were 0.7 +/- 0.1 micrograms ml-1 and 2.8 +/- 0.6 micrograms ml-1 for inhibition of uterine contractions and heart rate respectively. 5. In ovx, progesterone-treated late pregnant rats, nifedipine infusion produced similar serum concentrations to those of non-pregnant rats but completely abolished uterine contractions by 70 min. Maximum reductions of 30% in heart rate and blood pressure were observed.(ABSTRACT TRUNCATED AT 400 WORDS)     

The disposition of pyrimethamine base and pyrimethamine pamoate in the mouse: effect of route of administration

We have investigated the plasma pharmacokinetics and mass fate in mice, of pyrimethamine administered as either the base or as the poorly soluble pamoate salt, in each case by the intraperitoneal (i.p.) and subcutaneous (s.c.) routes. Following the administration of pyrimethamine base (i.p. and s.c.) and pyrimethamine pamoate (i.p.), maximum measured plasma levels of pyrimethamine were attained within 1 h, before declining monoexponentially. There was no significant difference between these three groups in the clearance (0.29 +/- 0.05, 0.30 +/- 0.03, 0.26 +/- 0.05 ml min-1), elimination half-life (4.5 +/- 0.5, 4.8 +/- 0.8, 4.9 +/- 0.5 h) and AUC (19.4 +/- 4.4, 17.3 +/- 2.2, 21.1 +/- 4.4 micrograms.h ml-1). By contrast, after s.c. dosage of pyrimethamine pamoate, drug absorption was significantly delayed, maximum plasma levels being reached after 4 h, these levels being approximately one-third of those in the other three groups. Absorption was however complete, as the values for AUC and clearance were not significantly different from the other groups. The pattern of faecal and urinary elimination of 14C radioactivity was unaffected by either dose site or formulation of pyrimethamine. The majority of the dose (44.5-64.2 per cent) was eliminated in the faeces suggesting extensive biliary excretion. Localization of 14C radioactivity in the major organs was negligible in all groups. Following each dose, between 85 and 98 per cent of the dose was accounted for. These studies indicate that of the four treatment groups only pyrimethamine pamoate on s.c. administration demonstrates a sustained release action from the dose site.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of lignocaine on arginine-vasopressin plasma levels: baseline or induced by frusemide.

1. To assess whether or not lignocaine influences baseline and frusemide-induced (5 mg kg-1) plasma concentrations of arginine-vasopressin (AVP), 2 groups of rabbits received an infusion of lignocaine (130 micrograms min-1 kg-1) for 6 h. Lignocaine-induced changes in AVP plasma concentrations were substantiated by measurement of diuresis and natriuresis and hepatic plasma flow, by means of an infusion of indocyanine green (ICG) (249 micrograms min-1 kg-1). 2. Baseline plasma AVP levels were 4.9 +/- 0.9 pg ml-1 (+/- s.e.), and following lignocaine, these values were reduced to 0.7 +/- 0.1 pg ml-1 (P less than 0.01). Frusemide increased AVP levels to 134.1 +/- 73.6 pg ml-1 (P less than 0.05) and lignocaine totally prevented this increase, e.g. mean AVP levels of 2.7 pg ml-1. 3. Lignocaine enhanced baseline diuresis secondary to an increase in free water clearance; none of the experimental conditions affected the diuresis and natriuresis induced by frusemide. 4. Frusemide reduced the hepatic plasma flow and this decrease was not reversed by the infusion of lignocaine. 5. It is concluded that in healthy rabbits lignocaine reduces baseline secretion of AVP and its antidiuretic effect; in addition, lignocaine prevents the rise in AVP induced by frusemide.     

Population study of triazolam pharmacokinetics.

The kinetics of a single 0.5 mg oral dose of the triazolobenzodiazepine hypnotic triazolam, were studied in 54 healthy young men aged 20-44 years, with a mean body weight of 77 kg. Triazolam kinetics were determined from multiple plasma concentrations measured during 14 h post-dose. The overall mean +/- s.e. mean (with range) kinetic variables were: peak plasma concentration, 4.4 +/- 0.3 (1.7-9.4) ng ml-1; time of peak, 1.3 +/- 0.1 (0.5-4.0) h after dose; elimination half-life, 2.6 +/- 0.1 (1.1-4.4) h; total AUC: 19.1 +/- 1.1 (4.4-47.7) ng ml-1 h; oral clearance, 526 +/- 38 (175-1892) ml min-1. All kinetic variables were consistent with Poisson distributions, based on the Kolmogorov-Smirnov Goodness of Fit test. None of the variables fit normal distributions. Four of five were consistent with a log normal distribution. Peak plasma level was highly correlated with clearance (r = -0.85, P less than 0.0001), and AUC (r = 0.85, P less than 0.0001) but not with body weight (r = 0.21, NS). Clearance and body weight were not correlated (r = -0.01). Triazolam clearance may vary widely even within a homogeneous group of healthy young men.     

The pharmacokinetics of HI-6 in beagle dogs

The pharmacokinetics of HI-6 were studied following intravenous administration to beagle dogs (n = 7). The bioavailability of two different strength intramuscularly administered doses was also determined in the same animals. After a 20 mg kg-1 intravenous dose, the mean (+/- S.D.) initial HI-6 plasma concentration was 93.1 +/- 10.8 micrograms ml-1. The mean half-life was 48.2 +/- 17.7 min, the mean total body clearance was 5.16 +/- 0.81 ml min-1 kg-1, the mean apparent volume of distribution was 0.37 +/- 0.20 l kg-1 and 61.2 +/- 14.6 per cent of the dose was excreted as unchanged drug. The pharmacokinetic constants calculated following the 20 mg kg-1 intramuscular doses of 250 and 25 mg ml-1 solutions were not significantly different from those obtained following the intravenous dose. Also, the areas under the plasma concentration versus time curves were not significantly different indicating 100 per cent bioavailability from the intramuscular route of administration.     

Pharmacokinetic-pharmacodynamic model for fantofarone cardiac and brachial haemodynamic effects in healthy volunteers

AIMS: To investigate the pharmacokinetics of SR 33671, the main active metabolite of the calcium antagonist fantofarone, and the relationships between its concentrations and pharmacodynamic effects after a single oral administration of two doses (100 and 300 mg) of fantofarone. METHODS: A placebo-controlled, randomized, double-blind and crossover study was performed in six healthy volunteers. SR 33671 plasma concentrations (C, ng ml-1 ) and effects (E) on heart rate (HR, beats min-1 ), PR interval duration (ms), brachial artery flow (BAF, ml min-1 ) and brachial vascular resistance (BVR, mmHg s ml-1 ) were determined repeatedly after drug intake. Haemodynamic effects were expressed as percent changes from initial values. Bi-exponential (pharmacokinetics), and linear [E=S.C+E0, for cardiac effects] or sigmoid [E=Emax.Cgamma/(CEgamma50+Cgamma ), for haemodynamic effects] models were fitted to individual data. RESULTS: Peak plasma concentrations and areas under the curve up to 24 h were (mean+/-s.d.) 16+/-10 ng ml-1 and 157.50+/-89.13 ng ml-1 h, and 63+/-11 ng ml-1 and 535.50+/-135.11 ng ml-1 h, after 100 and 300 mg, respectively. Terminal half-life was approximately 4 h. For pharmacodynamics, we obtained: S=-0.201+/-0.057 beats min-1/ng ml-1 for HR, S=0.526+/-0.114 ms/ng ml-1 for PR interval duration, Emax=42+/-6%, CE50=8.8+/-7.2 ng ml-1 and gamma=2.2+/-1.5 for BAF, and Emax=-28+/-4%, CE50=5.8+/-5.1 ng ml-1 and gamma=3.4+/-1.8 for BVR. At a SR 33671 concentration of 15 ng ml-1, BVR is decreased by 27% whereas HR is reduced by less than 3 beats min-1 and PR interval duration is increased by less than 8 ms. CONCLUSIONS: Fantofarone is able to induce submaximal peripheral vasodilating effects at doses that are devoid of any clinically significant cardiac effect.     

The concentration-dependent disposition of intravenous p-aminohippurate in subjects with normal and impaired renal function.

1. The disposition and kinetics of p-aminohippuric acid (PAH) were studied in 27 healthy male volunteers, 10 healthy female volunteers and 10 patients with chronic renal impairment following rapid intravenous injection of 10 mg kg-1. In addition, the renal clearances of PAH and its metabolite N-acetyl-PAH were measured in 10 of the healthy male volunteers following conventional administration of PAH by loading dose and constant infusion, and in another eight during sequential 'step-up' and 'step-down' infusions intended to maintain low, medium and high plasma concentrations below the threshold for onset of saturation of tubular transport. 2. PAH was eliminated rapidly with a mean half-life of less than 30 min in the healthy volunteers and 72 min in the renal patients. The corresponding estimates for acetyl-PAH were 49 and 153 min. In both groups the rate of disappearance of PAH slowed progressively over the period of observation and there was no true log-linear terminal elimination phase. 3. In the healthy volunteers about 50% of the dose was excreted in the urine in 30 min with quantitative recovery in 3 h. In 8 h, 17% of the dose was recovered as acetyl-PAH. In the patients with renal impairment the 8 h recovery was only 83.6% of the dose with 26.9% of the total appearing as acetyl-PAH. 4. The volume of distribution (Vss) of PAH was 16-18 l in the healthy subjects and renal patients. Acetyl-PAH appeared to have a much larger distribution volume (mean 65.5 l in the healthy volunteers). 5. In the healthy volunteers the renal clearance of PAH fell dramatically from 599 +/- 115 ml min-1 1.73m-2 during the first hour after administration to 300 +/- 208 ml min-1 1.73 m-2 during the second hour (P < 0.001). The corresponding renal clearances of acetyl-PAH were 775 +/- 196 and 916 +/- 212 ml min-1 1.73 m-2. In the patients with renal impairment the renal clearance of PAH fell from 194 +/- 83 ml min-1 1.73 m-2 in the first hour to only 61 +/- 19 ml min-1 1.73 m-2 from 4 to 6 h. Over the same period there was no significant fall in the clearances of acetyl-PAH or total PAH (acetyl-PAH + PAH).(ABSTRACT TRUNCATED AT 400 WORDS)     

The pharmacokinetics of mecillinam and pivmecillinam in pregnant and non-pregnant women.

1. The pharmacokinetics of parenteral mecillinam (n = 27) and oral pivmecillinam (n = 12) were studied in pregnant (n = 27) and non-pregnant (n = 12) subjects. 2. In early pregnancy (9-14 weeks of gestation) the mean peak plasma drug concentration (Cmax = 19 +/- 9 micrograms ml-1) after an intravenous injection of 200 mg mecillinam was significantly lower (P less than 0.05) and the volume of distribution (V = 49 +/- 20.1) significantly larger (P less than 0.05) than in non-pregnant subjects (Cmax = 35 +/- 18 micrograms ml-1, V = 29 +/- 12.1). In late pregnancy (39-40 weeks of gestation) the plasma mean peak concentration (Cmax = (29 +/- 14 micrograms ml-1) after parenteral administration of 200 mg mecillinam was slightly lower and the volume of distribution (V = 65 +/- 29.1, V = 0.9 +/- 0.4 l kg-1) significantly larger than that in non-pregnant subjects (V = 0.4 +/- 0.3 l kg-1). Also after oral administration of 200 mg pivmecillinam, equimolar to 136.5 mg mecillinam, the mean peak plasma concentration in pregnant subjects (Cmax = 1.8 +/- 1.2 micrograms ml-1) was slightly lower than that in non-pregnant subjects (Cmax = 1.7 +/- 1.2 micrograms ml-1). 3. The mean half-life of elimination after parenteral administration of mecillinam was significantly longer during both early (t1/2,Z = 133 +/- 38 min, P less than 0.05) and late pregnancy (t1/2,Z = 107 +/- 41 min, P less than 0.05) as compared with the non-pregnant state (t1/2,Z = 75 +/- 21 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and pharmacodynamics of physostigmine in the rat after oral administration

The distribution, metabolism, and pharmacokinetics of physostigmine (Phy) and the time course of butyrylcholinesterase (BuChE) in plasma and cholinesterase (ChE) activity in brain and muscle and their relationship to Phy concentration were described after oral administration of 3H-Phy (650 micrograms kg-1) to rats. Physostigmine concentration vs time data was analyzed by nonlinear computer fitting program using one-compartment model. The absorption rate constant (ka) and elimination rate constant (ke) were found to be 0.1 +/- 0.07 min-1 and 0.036 +/- 0.024 min-1, respectively. Cpmax and tmax were 3.3 ng ml-1 and 16 min. The clearance (C1) was found to be 80.9 ml min-1kg-1. Half-life of Phy in brain, muscle, and liver were 33.4 min, 22.5, and 28 min, respectively. The bioavailability (F) was calculated to be 0.02 and the extraction ratio was found to be 0.98 indicating the 'first pass' effect. Butyrylcholinesterase activity in plasma was 76 per cent at 15 min and this activity did not change significantly up to 120 min. However, Phy concentration in plasma was very low; 2.89 ng ml-1 at 15 min and declined to 0.71 ng ml-1 at 90 min. Physostigmine concentration in brain peaked at 22 min to 2.85 +/- 1.09 ng g-1 and declined to 0.33 +/- 0.11 ng g-1 at 60 min. Cholinesterase activity in brain was 96 per cent, 82 per cent and 89 per cent at 10, 45, and 120 min, respectively. Physostigmine concentration in muscle was very low and the ChE activity in the muscle was 66.4 per cent of control at 45 min. The time course of Phy metabolism indicated that at 5 min most of the RA in the tissues was due to metabolites accounting for 94.6 per cent in plasma, 90 per cent in liver, 79.8 per cent in brain and 86.3 per cent in muscle. M1 appeared to be the major metabolite followed by eseroline. The results showed extremely low concentrations of Phy (200 times less in plasma and 350 times less in brain) after oral administration compared to our previous studies with the same dose after i.m. administration.