Baclofen prevents the increase of myocardial oxygen demand indexes evoked by the hypothalamic stimulation in rabbits

Summary The electrical stimulation of the paraventricular nucleus (PVN) of the hypothalamus in anaesthetized rabbits elicited important cardiovascular responses which were mainly characterized by increases in arterial pressure, dP/dt_max, and of the indexes of myocardial oxygen consumption, rate-pressure product (from 34±2 to 40±2 mmHg · bpm · 10^–3) and triple product (from 102±12 to 162±19 mmHg² · s^–1 · bpm · 10^–6). The hemodynamic alterations induced by PVN stimulation were similar to those observed during physical effort and stressful situations. Intracerebroventricular (0.1, 0.3 and 1 g · kg^–1) or intravenous administration (1, 3 and 10 mg · kg^–1) of baclofen, a selective GABA_B receptor agonist, induced a dose-related decrease in the peak values of dP/dt_max and of the indexes of myocardial oxygen consumption (rate-pressure and triple products) during the electrical PVN stimulation. After 1 g · kg^–1 baclofen (i.cv.), the peak value of the triple product during PVN stimulation was 101±21 as compared to 149±15 before treatment. At the 10 mg · kg^–1 dose (iv.), the triple product during stimulation only reached 90±20 vs. 150±20 before treatment. These results suggested that a type B GABAergic transmission system is involved in the modulation of central control of the cardiac function. Drugs modulating this system could therefore be designed to blunt the myocardial oxygen demand increases. Correspondence to P. Bousquet     

Studies on hydralazine

Summary After oral administration of a single 50 mg dose of hydralazine (Apresoline^®), the serum half-life (T1/2) and bioavailability (AUC_0–) were assessed in 16 healthy volunteers. The half-life was 2.57±0.14 h (S.E.) in 10 slow acetylators of sulphadimidine, and 2.18±0.15 h in 6 fast acetylators (difference not statistically significant). AUC_0– was significantly higher in slow acetylators, at 1.04±0.10 µg·hour·ml^–1, compared to 0.66±0.12 µg·hour·ml^–1 in the fast acetylators (p<0.025). Treatment with Apresoline^® 25 mg tid produced minimum serum concentrations at steady-state of 57.3±7.3 ng·ml^–1 and 33.4±4.2 ng·ml^–1 in 8 slow and 5 fast acetylators, respectively (p<0.05). The corresponding maximum concentrations were 228.8±20.3 ng·ml^–1 and 147.6±15.0 ng·ml^–1 in slow and fast acetylators, respectively (p<0.025). First-pass metabolism of hydralazine could explain the difference in bioavailability of the drug between fast and slow acetylators, without any corresponding difference in the elimination rate of the drug in the post-distributive phase.     

Accumulation Kinetics of Propranolol in the Rat: Comparison of Michaelis– Menten-Mediated Clearance and Clearance Changes Consistent with the “Altered Enzyme Hypothesis”

(+)-Propranolol was infused at two rates into the pyloric vein (a portal vein tributary) of 15 male Sprague Dawley rats until apparent steady-state conditions were established (i.e., 8 hr at each rate). One group (n = 7) received the high dose (40 µg/min/kg) first, and in the other group (n = 8) the low dose (20 µg/kg/min) was used to initiate treatment. Free and total serum concentrations of propranolol were measured. When the low dose was given first, the apparent steady-state concentrations achieved during low- and high-rate infusion steps were 166 ± 37 and 774 ± 235 ng/mL, respectively. These data are consistent with a simple Michaelis–Menten kinetic model and the key parameters of such a model (V _max and K _m) were estimated. However, a crucial test of such a model (and one which should give insight regarding the relevance of an altered enzyme hypothesis) is to reverse the order of infusion steps since, in a system controlled by Michaelis–Menten kinetics, the same steady-state concentrations should be achieved regardless of the order in which infusion steps are given. When the sequence of infusion rates was reversed, steady-state concentrations were 492 ± 142 and 298 ± 79 ng/mL for the high and low infusion rates, respectively. Clearly, a history of high-dose exposure reduces the intrinsic clearance of total drug (CL_SS) during a subsequent low-dose exposure (i.e., the apparent steady-state levels during the low-dose pyloric vein infusions were significantly different; P < 0.001). When these data were corrected for plasma protein binding, the same trends emerged. For example, the intrinsic clearance of free drug (CL_Uss) during low dose treatment, when this treatment was given first, was 27.4 ± 7.3 L/min/kg. However, when the low dose was given as the last step, CL_Uss was only 14.4 ± 5.6 L/min/kg. This highly statistically significant decrease in CL_Uss (P < 0.002) is inconsistent with any simple Michaelis–Menten model, but it is consistent with an altered enzyme hypothesis.     

Pharmacokinetics of quinidine and three of its metabolites in man

Disposition parameters of quinidine and three of its metabolites, 3-hydroxy quinidine, quinidine N-oxide, and quinidine 10,11-dihydrodiol, were determined in five normal healthy volunteers after prolonged intravenous infusion and multiple oral doses. The plasma concentrations of individual metabolites after 7 hr of constant quinidine infusion at a plasma quinidine level of 2.9±(SD) 0.3 mg/L were: 3-hydroxy quinidine, 0.32±0.06 mg/L; quinidine N-oxide, 0.28±0.03 mg/L; and quinidine 10,11-dihydrodiol, 0.13±0.04 mg/L. Plasma trough levels after 12 oral doses of quinidine sulfate every 4 hr averaged: quinidine, 2.89±0.50 mg/L; 3-hydroxy quinidine, 0.83±0.36 mg/L; quinidine N-oxide, 0.40±0.13 mg/L; and quinidine 10,11-dihydrodiol, 0.38±0.08 mg/L. Relatively higher plasma concentrations of 3-hydroxy quinidine metabolite after oral dosing probably reflect first-pass formation of this quinidine metabolite. A two-compartment model for quinidine and a one-compartment model for each of the metabolites described the plasma concentration-time curves after both i.v. infusion and multiple oral doses. Mean (±SD) disposition parameters for quinidine from individual fits, after i.v. infusion were as follows: V ₁ ,0.37±0.09 L/kg; ₁,0.094±0.009 min ^–1; ₂, 0.0015±0.0002 min^–1; EX2, 0.013±0.002 min^–1;clearance (Cl_Q),3.86±0.83 ml/min/kg. Both plasma and urinary data were used to determine metabolic disposition parameters. Mean (±SD) values for the metabolites after i.v. quinidine infusion were as follows: 3-hydroxy quinidine: formation rate constant k_mf,0.0012±0.0005 min ^–1,volume of distribution, V_m,0.99±0.47 L/kg; and elimination rate constant, k_mu 0.0030±0.0002 min ^–1.Quinidine N-oxide: k_mf,0.00012±0.00003 min ^–1; V_m,0.068±0.020 L/kg; and k_mu,0.0063±0.0008 min ^–1.Quinidine 10,11-dihydrodiol: k_mf,0.0003±0.0001 min ^–1; V_m,0.43±0.29 L/kg; and k_mu,0.0059±0.0010 min ^–1.Oral absorption of quinidine was described by a zero order process with a bioavailability of 0.78. Concentration dependent renal elimination of 3-hydroxy quinidine was observed in two out of five subjects studied.This work was supported by funds from the grants GM 26691 and GM 28072 from the National Institute of General Medical Sciences, NIH. A. Rakhit was the recipient of a Training Grant Traineeship from NIH. T. W. Guentert is grateful for support from the Swiss National Science Foundation.Professor Sidney Riegelman. deceased April 4, 1981.     

Interaction between clonidine and physostigmine in normal rats and in rats after sinoaortic denervation

Summary Clonidine (3–30 g · kg^–1, i.v.) induced a fall in mean arterial pressure in rats after sinoaortic denervation but not in sham-operated animals. Moreover, sinoaortic denervation reduced the bradycardic action of this antihypertensive drug. Pressor and tachycardic response to physostigmine (60 g · kg^–1, i.v.) were greater in denervated than in sham-operated rats. The increase of mean arterial pressure was 26.2 ± 2.2 mm Hg in sham-operated rats (n = 12) and 53.8 ± 2.0 mm Hg in denervated rats (n = 12, P < 0.005).Pretreatment with 3 g · kg^–1 (i. v.) of clonidine did not alter the pressor response to physostigmine (60 g · kg^–1) in either of the two groups; 10 and 30 g · kg^–1 of clonidine reduced the physostigmine-induced increase of mean arterial pressure in sham-operated rats but enhanced the pressor response in denervated animals. Furthermore, an ineffective dose of physostigmine (30 g - kg^–1 i.v.) induced a pressor response after pretreatment with clonidine (10 gg · kg^–1) in denervated rats.Clonidine (10 g · kg^–1) did not affect the pressor effect of 1,1 dimethyl-4-phenylpiperazinium iodide (DMPP: 50 g · kg^–1 i.v.) or phenylephrine (4 g · kg ^–1, i.v.) in either group.The anticholinergic effect of clonidine in sham-operated rats may be explained by an inhibitory action on the release of acetylcholine in several brain structures but the facilitatory effect of clonidine observed in denervated animals is not clear. The results did not suggest a peripheral involvement in this facilitatory effect. Send offprint requests to M. A. Enero at the above address     

Dose dependent methotrexate elimination following bolus intravenous injection

Summary The pharmacokinetics of methotrexate have been assessed at two dose levels in six patients recciving the drug for treatment of malignant disease. Each patient received bolus intravenous doses of 25 mg and 100 mg given at least one week apart, the order of administration being random. Blood and urine were collected until 48 h for methotrexate analysis by radioimmunoassay and data analysed by a model-independent pharmacokinetic approach. In each patient area under the methotrexate serum concentration-time curve (o to ) increased out of proportion to the increase in methotrexate dose. This was reflected in a mean clearance value after the 100 mg dose of 31±16 (SD) ml · min^–1 compared with a mean clearance of 62±19 ml · min^–1 following injection of 25 mg methotrexate. Renal clearance of methotrexate was markedly lower following the 100 mg dose (18±6 ml · min^–1) than after 25 mg (53±19 ml · min^–1). Saturation of the proximal tubular organic acid transport system is the likely cause of methotrexate's capacity limited elimination.     

The pharmacokinetics ofα-human atrial natriuretic polypeptide in healthy subjects

Summary We have analysed the pharmacokinetics of-human atrial natriuretic polypeptide (-hANP) in healthy subjects, using a two-compartment open model following bolus intravenous injection. The plasma half-times for the fast and slow components were 1.7±0.07 min and 13.3±1.69 min respectively. V₁ (the volume of the central compartment), V_z (volume of distribution) and V_ss (volume of distribution at steady-state) were 5370±855 ml (89.5±14.3 ml·kg^–1), 32000±4620 ml (533±77.0 ml·kg^–1), and 11900±1530 ml (198±25.5 ml·kg^–1) respectively. The mean plasma clearance was 1520±121 ml·min^–1 (25.4±2.0 ml·min^–1·kg^–1.     

Plasma glucose lowering effect of spartein sulphate infusion in non-insulin dependent (Type 2) diabetic subjects

Summary Sparteine sulphate, given i.v. as a bolus of 15 mg/ml plus 90 mg in 0.9% NaCl 100 ml over 60 min, increases plasma insulin and decreases plasma glucose and adrenaline in non-insulin dependent (Type II) diabetic subjects. The hypoglycaemic effect was also evident in the presence of a high plasma glucose level produced by Biostator changing glucose infusion from 20.2±2.8 to 26.4±4.2 mg · kg^–1 · min^–1 (p<0.01), and it was potentiated by simultaneous infusion of arginine.No additional effect of sparteine on the peripheral sensitivity to insulin were detected by the euglycaemic, hyperinsulinaemic glucose clamp technique, as the glucose infusion rate (3.1±0.8 vs 2.6±1.2 mg · kg^–1 · min^–1) was not statistically significant different in the last 60 min of the experiment.It is concluded that sparteine sulphate enhances -cell secretion, causing a fall in the plasma glucose concentration.     

Pharmacokinetic interaction of chloroquine and methylene blue combination against malaria

Objective The combination of chloroquine and methylene blue is potentially effective for the treatment of chloroquine-resistant malaria caused by Plasmodium falciparum. The aim of this study was to investigate whether methylene blue influences the pharmacokinetics of chloroquine.Methods In a randomized, placebo-controlled, parallel group design, a 3-day course of therapeutic oral doses of chloroquine (total 2.5 g in male, 1.875 g in female participants) with oral co-administration of placebo or 130 mg methylene blue twice daily for 3 days was administered to 24 healthy individuals. Chloroquine, desethylchloroquine, and methylene blue concentrations were determined by means of HPLC/UV or LC/MS/MS assays in whole blood, plasma, and urine for 28 days after the last dose.Results During methylene blue exposure, the area under the chloroquine whole blood concentration–time curve normalized to body weight (AUC_{0-24 h}/BW) yielded a trend of reduction (249±98.2 h g l^–1 kg^–1 versus 315±65.0 h g l^–1 kg^–1, P=0.06). The AUC_{0-24 h}/BW of desethylchloroquine was reduced by 35% (104±40.3 h g l^–1 kg^–1 versus 159±66.6 h g l^–1 kg^–1, P=0.03), whereas the metabolic ratio between chloroquine and desethylchloroquine remained unchanged (2.25±0.49 versus 1.95±0.42, P=0.17). The renal clearance of chloroquine and the ratio between chloroquine in whole blood and plasma remained unchanged (P>0.1).Conclusion Oral co-administration of methylene blue appears to result in a small reduction of chloroquine exposure which is not expected to be clinically relevant and thus represents no concern for further development as an anti-malarial combination.     

Plasma concentrations of pralidoxime methylsulphate in organophosphorus poisoned patients

Using pharmacokinetic data from healthy human volunteers in a bicompartmental pharmacokinetic model, a repeated dose scheme for pralidoxime methylsulphate (Contrathion^®) was developed producing plasma levels remaining above the assumed therapeutic concentration of 4 mg·1^–1. Using the same data, it was found that a concentration of 4 mg · 1^–1 could also be obtained by a loading dose of 4.42 mg · kg^–1 followed by a maintenance dose of 2.14 mg · kg^–1 · h^–1. In order to study the pharmacokinetic behaviour of pralidoxime in poisoned patients, this continuous infusion scheme was then applied in nine cases of organophosphorus poisoning (agents: ethyl parathion, ethyl and methyl parathion, dimethoate and bromophos), and the pralidoxime plasma levels were determined. The mean plasma levels obtained in the various patients varied between 2.12 and 9 mg·1^–1. Pharmacokinetic data were calculated, giving a total body clearance of 0.57±0.271· kg^–1· h^–1 (mean ± SD), an elimination half-life of 3.44±0.90 h, and a volume of distribution of 2.77±1.451 ·kg^–1.     

Opioid receptor agonists activate pertussis toxin-sensitive G proteins and inhibit adenylyl cyclase in canine cardiac sarcolemma

Although both opioid receptors and endogenous opioids are abundant in cardiac tissues, the signal transduction pathways of opioids in cardiac sarcolemmal membranes have yet to be identified. In highly purified canine cardiac sarcolemmal membranes, binding of the opioid receptor antagonist [³H]diprenorphine and effects of , and agonists on low K_m GTPase and adenylyl cyclase were measured. Equilibrium binding of [³H]diprenorphine revealed a maximal binding capacity of 7.2 pmol/mg protein and a K_d of 1.3 nmol/1. In the presence of GTP, (D-Pen^2,5, p-Cl-Phe⁴)enkephalin and (D-Arg⁶)dynorphin A 1-13 fragment both inhibited adenylyl cyclase by 20–25% (from 206 ± 30to164 ± 28 pmol·min^{– 1}·mgprotein^–1, EC₅₀6 mol/Landfrom254 ± 109to204 ± 90 pmol·min^{– 1}·mg protein^–, EC₅₀ 8 pmol/L, respectively; P<0.001). Both substances stimulated low Km GTPase by 20%and13%,respectively(from12.7 ± 3.0 to 15.2 ± 3.7 pmol·min^–1.mgprotein^–1,EC₅₀ 12 mol/L, P<0.01, and from 9.1 ± 2.8 to 10.4 ± 3.2 pmol-min^{– 1}·mg protein^–1, EC₅₀ 6 mol/L, P<0.05, respectively). These effects were blocked by the opioid receptor antagonist naltrexone and by pretreatment of sarcolemmal membranes with pertussis toxin. The opioid receptor agonists (D-AIa², Me Phe⁴, Gly-[ol]⁵)enkephalin and morphiceptin had no effect on either cardiac adenylyl cyclase or low Km GTPase activities. These data suggest that in cardiac sarcolemma, opioid receptors are coupled to pertussis toxin sensitive G proteins and mediate inhibition of adenylyl cyclase activity.     

Sensitivity of residual nephrons to high dose furosemide described by diuretic efficiency

Ten haemodialysis (HD) patients with a median residual creatinine clearance (CL_CR) of 1.9 ml·min^–1·1.73 m^–2 (range 0.6–5.3) were treated with oral furosemide (F) 2.0 g. Overall-efficiency (O-E, daily sodium excretion/total urinary F) and total-efficiency (-E, increase in daily sodium excretion/total urinary F) were measured on the last 24 hours of each interdialysis interval. In addition, O-E was measured during the complete interdialysis interval in 10 HD patients with a median CL_CR of 5.6 ml·min^–1·1.73 m^–2 (range 0.7–6.8) treated for 1 year with a fixed oral dose of F between 250–1000 mg (median 625 mg).In the short study the median O-E was 10.6 mmol·mg^–1 (range 1.9–22.0) and -E 6.2 mmol·mg^–1 (range 1.3–11.2). The fractional excretion of sodium FE_Na was significantly increased from 9.6% (range 4.1–22.9) to 27% (range 14.6–56.2) during F treatment. A positive correlation was found between the basal FE_Na and -E. In the long-term study median O-E was 6.4 mmol·mg^–1. O-E and FE_Na showed no change over time although median RCC decreased from 5.6 to 1.9 ml·min^–1·1.73 m^–2 and median F excretion from 11.8 to 7.5 mg per day.It can be concluded that diuretic efficiency in haemodialysis patients is dependent on FE_Na and the state of hydration during the interdialysis interval.     

Pharmacokinetics of rufloxacin in healthy volunteers

Summary The plasma and urine kinetics of rufloxacin were assessed in healthy volunteers after single (100, 200, 400 and 800 mg) and multiple (300 mg followed by 150 mg daily, Group 1, and 400 mg followed by 200 mg daily, Group 2) oral doses. The kinetics of a single oral dose of 800 mg was assessed in fasting and non-fasting subjects to assess the influence of food intake on drug absorption.The AUCs were 134, 266 and 375 g · h · ml^–1 after 100, 200 and 400 mg, respectively. The AUC after 800 mg p. o. was 715 g · h · ml ^–1 in fasting subjects and 614 g · h · ml^–1 in non-fasting subjects. The parameters of the model and the mean renal clearance values indicated some departure from linearity in rufloxacin kinetics. After multiple doses the plasma drug levels during the 6th treatment day were similar to those after the first dose in Group 1 and were about 30–40% higher after the first dose in Group 2. The half-lives after the last dose were much shorter than those estimated in the single dose studies (33–36 h and 50–80 h, respectively).     

Pharmacokinetics of ibuprofen in febrile children

Summary Ibuprofen may be an alternative to acetaminophen to control fever in children but little is known about its pharmacokinetics in pediatric patients. We studied 17 patients (age 3–10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. Ibuprofen liquid was given as a single dose, 5 mg/kg (9 patients) or 10 mg/kg (8 patients). Multiple blood samples were collected over 8 hours and analyzed by HPLC.The maximum observed serum concentrations of ibuprofen ranged from 17–42 m·ml^–1 at 5 mg·kg^–1 and 25–53 m·ml^–1 at 10 mg·kg^–1 doses. Pharmacokinetics did not appear to be affected by ibuprofen dose. Mean t_max, oral clearance and elimination half life were 1.1 h, 1.2 ml·min^–1·kg^–1, and 1.6 h, respectively in patients at 5 mg·kg^–1 doses; the corresponding values were 1.2 h, 1.4 ml·min^–1·kg^–1, and 1.6 h in those receiving 10 mg·kg^–1 doses. There was no relationship between age and ibuprofen kinetics. No adverse effects occurred in any patients.These data suggest that ibuprofen pharmacokinetics may not be affected by dose between 5 and 10 mg/kg or age between 3 and 10 years.     

Binding of a metabolite of triflusal (2-hydroxy-4-trifluoromethylbenzoic acid) to serum proteins in rat and man

Summary 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) is the main active metabolite of the platelet anti-aggregant drug triflusal. Its binding to plasma proteins of rats and healthy volunteers in vitro and in vivo has been studied.Rats were given a single oral dose of 50 mg·kg^–1 triflusal and the healthy volunteers received 300 mg as a single oral dose or a multiple dose regimen of 600 mg every 24 h and 300 mg every 8 h, both for 13 days. Protein-free HTB was obtained by ultrafiltration. Unbound and total HTB concentrations were determined by HPLC.HTB was primarily bound to albumin in plasma. The Scatchard plots suggested two types of binding sites for HTB on the albumin molecule. In rats, the binding constants (K=intrinsic affinity constant, n=number of binding sites) were K₁=1.4×10⁵ l·mol^–1, n₁=1.23, and K₂=4.1×10³ l·mol^–1 and n₂=3.77. The mean plasma concentration in rats after oral administration was 185 (37) g·ml^–1 (protein-free HTB: 2.44 (0.77)%). The binding constants in human plasma were K₁=4.7×10⁵ l·mol^–1, n₁=1.93, K₂=4.3 l·mol^–1 and n₂=4.28.The plasma HTB concentration in man (n=8) was 35 g·ml^–1 (C_max) after a single oral dose of triflusal 300 mg, 172.96 g·ml^–1 (C_max·ss) during the multiple dosage regimen of 300 mg every 8 h, and 131 g·ml^–1 (C_max·ss) during the multiple oral dose regimen of 600 mg every 24 h. Unbound HTB ranged from 0.27 to 0.43%, depending on dose. HTB had high affinity for plasma albumin, which was not saturable after therapeutic doses. It showed linear elimination.     

Influence of isoprenaline and salbutamol on the threshold of electrically inuced ventricular fibrillation in anaesthetized guinea pigs

Summary Fibrillation threshold and heart rate were measured after increasing doses of (–)-isoprenaline and (±)-salbutamol. The initial values of 212±10 A (x±SEM) and 211±10 A were decreased to 74±10 A by low doses of (–)-isoprenaline (10^–11 to 10^–10 moles/kg i.v.), and to 89±11 A by (±)-salbutamol (10^–9 to 10^–8 moles/kg i.v.). Higher doses, paradoxically, increased fibrillation threshold to initial values, (–)-isoprenaline: 2×10^–9 moles/kg; (±)-salbutamol: 2×10^–6 moles/kg. A linear increase in heart rate per 10-fold increase of either drug was observed, (–)-isoprenaline: 25 beats·min^–1; (±)-salbutamol: 14 beats·min^–1. The apparent ₂-selective property of salbutamol is documented by its low potency in changing fibrillation threshold and heart rate.     

Pharmacokinetics and pharmacodynamics of diprophylline

Diprophylline is used in many countries as a bronchodilator. It is an N-substituted theophylline derivative which does not release theophyllinein vitro orin vivo. It therefore has its own pharmacokinetic and pharmacodynamic properties. In a cross-over study in ten healthy volunteers serum concentrations and urinary excretion were studied after administration of diprophylline.Its serum decay after intravenous administration shows two-compartment kinetics with a rapid distribution. The-phase lasted on average 0.75 h and was 0.427±0.118 h^–1, corresponding with a-phase half-life of 1.7±0.4 h. The mean volume of distribution was 0.70±0.20 l/kg, total body clearance 0.29±0.09 l.kg^–1.h^–1. About 84% of the drug is excreted unchanged in the urine. A comparison of the area under the curve suggests that the drug was almost completely absorbed from the gastro-intestinal tract. Its bioavailability is about 90%. Mean renal clearance values are higher than paired creatinine clearance values, which is an indication for active renal transport.Peak levels of diprophylline were 7.4±2.2 mg/l at about 30 min after oral administration. The normal dose advocated is 200–400 mg three times a day. Inin vitro studies and in pharmacological animal studies diprophylline appears to be much less active than theophylline. Consequently estimated effective dosages are irrationally high.In honour of ProfessorHuizinga on the occasion of his retirement.     

The pharmacokinetics of midazolam in man

Summary Midazolam, a new water-soluble benzodiazepine, was administered as: i) 5 mg intravenously, ii) a 10-mg oral solution and iii) a 10-mg oral tablet, to six volunteers whose informed consent had been obtained. Midazolam plasma concentrations were measured using an electron-capture gas-liquid chromatographic assay. After 5-mg intravenous midazolam, subjects fell asleep within 1–2 min and continued to sleep for an average of 1.33 h. After oral midazolam intake (solution or tablets), drowsiness appeared after a average of 0.38 h (range 0.25–0.55 h) and sleep continued for an average of 1.17 h. The time to reach peak plasma midazolam concentration after the 10-mg solution dose (0.37±0.45 h) did not differe significantly (t=2.04, df=10,p>0.05) from the time to reach peak plasma midazolam level after the 10-mg tablet dose (0.74±0.45 h). The terminal half-life, (t_1/2), of midazolam in plasma was 1.77±0.83 h and there was no significant difference between the mean terminal half-life values obtained for the three midazolam formulations. The mean total clearance (Cl), of midazolam after 5-mg intravenous administration was 0.383±0.094 l·kg^–1·h^–1. The first pass effect, F, determined experimentally (0.36±0.09) indicated the substantial first pass metabolism of midazolam. The percentage of the midazolam dose excreted unchanged in urine in four subjects during the 0-8-h urine collection interval was very small (0.011%–0.028%).     

Toxicokinetics of methyl parathion and parathion in the dog after intravenous and oral administration

Methyl parathion (20 mg · kg^–1 intravenously and orally) and parathion (5 mg · kg^–1 intravenously and 10 mg · kg^–1 orally) were given to non-anesthetized dogs and the serum concentrations were followed in function of time. For both substances a low bioavailability after oral administration was found.In other dogs radioactivity was followed in urine after oral and after intravenous administration of labeled methyl parathion or parathion. The results suggest a good gastro-intestinal absorption of the substances.In anesthetized dogs which were given methyl parathion or parathion intravenously, high hepatic extraction ratios were found, suggesting that the low systemic availability after oral administration can be explained by an important hepatic first-pass extraction.Binding of methyl parathion and parathion to dog serum, to human serum and to a solution of human albumin was determined with equilibrium dialysis. In both species a high binding (>90%) was found for both substances and there was no concentration-dependency in the concentration range used (0.2–30 g · ml^–1). In man and in dog the serum protein binding of parathion was about 5% higher than that of methyl parathion.     

Biliary elimination of indomethacin in man

Summary The biliary elimination of indomethacin 100 mg p.o. has been investigated in patients with a T-tube drain after cholecystectomy, who had normal or abnormal liver function (Group In=5, and Group IIn=4, respectively). In plasma, the concentration maximum (Group I 9.5±1.4 µmol·1^–1; Group II 19.4±3.8 µmol·1^–1) and the total clearance (Group I 1.56±0.28 ml·min^–1·kg^–1, Group II 0.5±0.06 ml·min^–1·kg^–1) were significant different in the two groups. The bile:plasma ratio (bpr) in Group I was 1.3±0.33 and 10.1±3.2, respectively, for indomethacin (In) and conjugated In. The conjugated fraction of In was 87.5±1.9% of the total concentration. In Group II the bpr was lower (0.65±0.1). In is eliminated in bile by diffusion and conjugated In by active secretion. In Group I 0.99±0.1 mg In and 6.1±0.7 mg conjugated In and in Group II 2.1±0.3 mg In (p<0.05) were eliminated in bile. No influence of In on the biliary lipids was observed or on the bile acid-independent fraction of bile flow. It is concluded that the total plasma clearance of In was dependent of liver function. Conjugated In undergoes enterohepatic circulation.