Lack of efficacy of cimetidine and ranitidine as inhibitors of tolbutamide metabolism

Summary We investigated the effect of 4 days pretreatment with cimetidine (1.2g daily) and ranitidine (0.3 g daily) on tolbutamide disposition in an open randomised, cross-over study design involving 8 healthy adult male volunteers.Control half-life of tolbutamide 6.29 h was not significantly altered by cimetidine (6.93 h) or ranitidine (6.97 h). The corresponding apparent oral clearance (ml·min^–1·kg^–1) were not significantly different: 0.26 (control), 0.24 (cimetidine) and 0.25 (ranitidine). Apparent volume of distribution was also unaltered 0.140l·kg^–1 (control), 0.141l·kg^–1 (cimetidine) and 0.146l·kg^–1 (ranitidine).It is suggested that the hepatic monooxygenase isozyme that catalyses the rate-limiting conversion of tolbutamide to its hydroxy derivative is not susceptible to the inhibitory effect of cimetidine or ranitidine.     

Selective inhibition of drug oxidation after simultaneous administration of two probe drugs,antipyrine and tolbutamide

Summary The effects of sulphaphenazole, cimetidine and primaquine on the disposition of antipyrine and tolbutamide in healthy volunteers have been investigated. The model substrates were administered simultaneously in order more clearly to define any selective effects of the potential inhibitors. Sulphaphenazole produced a significant increase in the half-life of tolbutamide (7.10 to 21.50 h) and a correponding decrease in its clearance (0.260 to 0.084 ml·min^–1·kg^–1). Clearance to hydroxytolbutamide (OHTOL) and carboxytolbutamide (COOHTOL) was also significantly decreased.In contrast, sulphaphenazole had no effect on the disposition of antipyrine. Administration of cimetidine did not significantly alter the disposition of either model drug. However, a 1.6-times higher dose of cimetidine did increase the half lives both of tolbutamide and antipyrine (6.21 to 9.04 h and 14.2 to 19.2 h, respectively) and decrease their clearance (0.226 to 0.148 and 0.50 to 0.31 ml·min^–1 kg^–1, respectively). Clearance to OHTOL and hydroxymethylantipyrine (HMA) was reduced.A single dose of primaquine had no demonstrable effect on tolbutamide disposition whereas the half-life of antipyrine was increased (12.1 to 15.0 h) and its clearance decreased (0.63 to 0.38 ml·min^–1·kg^–1). The partial clearance to HMA, 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) was also significantly reduced.The two main inferences are first, that tolbutamide and antipyrine are metabolished by different forms of cytochrome P-450, and second that a battery of model substrates is needed to investigate the inhibitory effects of a drug in man.     

Lack of relationship between tolbutamide metabolism and debrisoquine oxidation phenotype

Summary The oxidative metabolism of tolbutamide was studied in 13 healthy subjects of known debrisoquine phenotype. Three were poor (PM) and ten were extensive (EM) metabolisers of debrisoquine.The mean values for total plasma clearance, elimination half-life, and metabolic clearance were 0.26 ml·min^–1·kg^–1, 3.4 h, and 0.17 ml·min^–1. kg^–1 in PM subjects and 0.22 ml·min^–1·kg^–1, 4.3 h and 0.15 ml·min^–1·kg^–1 in EM subjects. Total urinary recovery (% of dose) and ratio of hydroxy- to carboxytolbutamide were 69.4% and 0.219 respectively in PM subjects and 70.9% and 0.226 in EM subjects. There were no statistically significant differences between EM and PM metabolisers for any of these parameters. In addition there was no correlation between the debrisoquine metabolic ratio and tolbutamide urinary metabolite recovery or plasma clearance.These data indicate that hydroxylation of debrisoquine and tolbutamide are not catalyzed by the same enzyme.The ratio of hydroxy- to carboxytolbutamide in our subjects, and in other recent studies, suggests that some previous publications were inaccurate and their conclusions about the genetic control of tolbutamide metabolism were incorrect.     

Pharmacokinetics of ciprofloxacin tablets in renal failure; influence of haemodialysis

Summary The pharmacokinetics of ciprofloxacin has been studied after a single oral dose of 500 mg given to 5 normal subjects (N) and to 15 patients grouped according to their residual renal creatinine clearance: Group I, 8–30 ml·min^–1, Group II, <8 ml·min^–1, and Group III, haemodialysed patients studied twice — during an interdialysis period (IIIa) and in a 4 h haemodialysis session (IIIb). Ciprofloxacin was assayed by reverse phase HPLC using a spectrofluorimetric detection. The peak plasma concentration (2–5 mg·l^–1) was reached within 2 h after drug administration. Apparent volume of distribution, 6.6 (N), 5.0 (I), 2.7 (II) and 4.2 (IIIa) l·kg^–1 and total plasma clearance, 770 (N), 440 (I), 378 (II) and 314 (IIIa) ml·min^–1 were decreased in relation to the degree of renal impairment. Mean plasma half-lives for patients in the 4 groups were 7.3 (N), 10.4 (I), 7.2 (II) and 9.3 (IIIa) h. In groups N, I and II, 40, 16 and 8% of the administered dose was eliminated through the kidney, with mean renal clearances of 305±63,61±21 and 21±3 ml·min^–1. A linear relationship was found between the renal clearance of ciprofloxacin and the glomerular filtration rate (r=0.75,n=15). Ciprofloxacin was partly removed by haemodialysis (IIIb): the dialyser extraction ratio was 23% and the dialysis clearance was 40 ml·min^–1.     

Pharmacokinetics of cimetidine after subchronic administration

Summary The influence of cimetidine on its own pharmacokinetics after subchronic administration was assessed in 8 healthy volunteers, aged 26–29 years. On control Day 1, each subject received cimetidine 300 mg i.v., and serum and urine samples were obtained. Each subject was initiated on cimetidine 600 mg b.i.d. orally for 2 weeks. There were 3 further study days repeated after 1 and 2 weeks of cimetidine dosing and 1 week after stopping cimetidine. There was no significant difference in the mean total body clearance of cimetidine among the 4 study days. Mean elimination t_1/2 and V were similarly unchanged. However mean renal clearance (CL_R) and f_e were significantly increased following 2 weeks of drug dosing (CL_R 5.41 ml·min^–1 kg^–1; f_e 0.61) compared to control (CL_R 4.00 ml·min^–1·kg^–1; f_e 0.48). Although the non renal clearance was reduced from control values of 4.29 to 3.51 ml·min^–1·kg^–1 following 2 weeks of dosing the difference was not significant. Dosage adjustment of cimetidine appears unnecessary after short-term dosing in the presence of normal renal function.     

Polymorphic flecainide disposition under conditions of uncontrolled urine flow and pH

Summary The pharmacokinetics of R- and S-flecainide have been determined in five poor (PM) and five extensive (EM) metabolisers of sparteine/debrisoquine under conditions of uncontrolled urine flow and pH. The half-lives of R- and S-flecainide in PMs (R 19.3 h; S 16.1 h) were approximately twice those observed in EMs (R 8.8 h; S 9.1 h). The apparent oral clearances of R- and S-flecainide were lower in PMs (R 313 ml·min^–1; S 379 ml·min^–1) than in EMs (R 783 ml·min^–1; S 828 ml·min^–1). The renal clearance, however, was comparable for both enantiomers in both EMs and PMs, and therefore the phenotypic differences in flecainide disposition observed must be due to differences in metabolic clearance. The nonrenal clearance of both enantiomers was significantly lower in poor (R 123 ml·min^–1; S 201 ml·min^–1) relative to extensive metabolisers (R 533 ml·min^–1; S 586 ml·min^–1). The partial clearance to the two major metabolites meta-O-dealkylated flecainide (MODF) and the meta-O-dealkylated lactam of flecainide (MODLF) was significantly lower in poor (62 ml·min^–1) than extensive (267 ml·min^–1) metabolisers.The impairment in flecainide metabolism in poor metabolisers of sparteine/debrisoquine has therefore been confirmed. Under conditions reflecting the clinical situation the difference in disposition between EMs and PMs would be considerable. However, it may be predicted that at standard doses concentrations greater than 1000 ng·ml^–1 would not be attained in the PMs studied. The serum protein binding of R- and S-flecainide was studied in each subject and no differences between the enantiomers or the phenotypes were observed (Free fraction EM: R 0.43; S 0.42; PM R: 0.46; S: 0.46). Enantioselective disposition was noted in all PMs studied, due to a significantly lower nonrenal clearance of the R-enantiomer. In extensive metaboliser subjects, considerable interindividual variation in the enantioselective disposition of flecainide was noted, ranging from metabolism favouring either enantiomer to the absence of any selectivity.Presented in part at the 23rd Annual Meeting of the Australasian Society of Clinical and Experimental Pharmacologists, Sydney, 4–6 December, 1989     

Digoxin-diltiazem interaction: A pharmacokinetic evaluation

Summary The pharmacokinetics of digoxin were studied before and after a 2 week course of diltiazem, 30 mg four times daily, in 7 healthy volunteers. Each subject received an IV dose of digoxin before starting diltiazem and again on day 15 of the study. Diltiazem was continued until all sera and urine were collected. During the control and diltiazem phases, respectively, the terminal elimination rate constants were 0.0231±0.007 h^–1 and 0.0254±0.007 h^–1, the volumes of distribution were 10.5±3.95 l/kg and 10.2±3.26 l/kg, and the total body clearances were 3.72±0.78 ml·min^–1·kg^–1 and 4.09±0.94 ml·min^–1·kg^–1. None of these pharmacokinetic parameters of digoxin were significantly different before or during diltiazem administration. Overall, there does not appear to be an interaction between digoxin and diltiazem.     

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.     

Alteration by burn injury of the pharmacokinetics and pharmacodynamics of cimetidine in children

Summary We have studied the mechanisms of the increased dosage requirements of the H₂-receptor antagonist cimetidine in paediatric burned patients in a pharmacokinetic and pharmacodynamic study.Cimetidine (10–15 mg·kg^–1) was given to 21 burned children and multiple blood samples were obtained for determination of plasma cimetidine concentrations and pharmacokinetic analysis.The relation of gastric pH to plasma cimetidine concentrations was studied in five of these children who had nasogastric tubes. In an additional four patients the effects of cimetidine on gastric pH were studied during a continuous infusion of cimetidine, which maintained steady-state plasma cimetidine concentrations above 0.5 µg·ml^–1.The mean (SEM) clearance of cimetidine in burned children was 16.22 ml·kg^–1 and cimetidine half-life was 1.06 h. The cimetidine clearance and half-life values were significantly higher in burned children compared with our previously reported values for normal adult patients, 8.2 ml·min·kg^–1 and 2.21 h respectively.Endogenous creatinine clearance normalized to 70 kg in burned children was 190 ml·min^–1. In burned children 41% of the dose of intact cimetidine was excreted during 8 h of the study compared with 45% excretion during 24 h in healthy adult controls previously reported. The correlation coefficient between creatinine and cimetidine clearances was 0.93 (r ²=0.85).The plasma concentration of cimetidine needed to increase gastric pH to 4.0 was 1.0 µg·ml^–1, which contrasts with the value of >0.5 µg·ml^–1 required for adult burned patients.These findings support the hypothesis that the higher dosage requirements of cimetidine in burned children is due both to enhanced elimination kinetics and to alterations in target organ sensitivity, requiring higher than normal plasma concentrations for the desired effect. In burned children Cimetidine should be given in higher doses and/or more frequently.     

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.     

Pharmacokinetics of ranitidine in patients undergoing haemofiltration

Summary The pharmacokinetics of ranitidine was investigated in 11 patients with acute or end stage renal failure during haemofiltration. Each patient received 50 mg ranitidine i.v.The mean distribution and elimination half lives were 0.13 and 2.57 h, respectively. The total body clearance (CL) and volume of distribution (V_z) were 298 ml·min^–1 (5.19 ml·min^–1·kg^–1) and 1.081·kg^–1, respectively. About 17.1% of the administered dose was removed by haemofiltration (in approximately 201 filtrate). Five of the patients still had some urine output and they excreted 0.1 to 11.8% of the dose in urine in 24 h. The haemofiltration clearance was 66.9 ml·min^–1 at a filtrate flow rate of 86 ml·min^–1, corresponding to a mean sieving coefficient of 0.78 (n=6). As plasma concentrations were still in an effective range after haemofiltration, dose supplementation is not recommended.     

Pharmacokinetics of dexamethasone in premature neonates

Objective: Dexamethasone is frequently used in premature neonates with bronchopulmonary dysplasia, however little is known about its disposition in this population. Methods: We evaluated the pharmacokinetics of dexamethasone in 9 premature neonates with a mean gestational age of 27.3 weeks and a postnatal age of 21.8 days. Results: There was a strong relationship between clearance (4.96 ml·min^–1·kg^–1) and gestational age (r=0.884). Pharmacokinetic parameters were grouped based on a gestational age of less than 27 weeks (Group I) and greater than 27 weeks (Group II). Mean clearance in group I and group II was 1.69 and 7.57 ml·min^–1·kg^–1, respectively. Mean distribution volume in group I and II was 1.26 and 2.19 l·kg^–1, respectively. No significant relationships were noted between the disposition of dexamethasone and ventilator requirements or adverse effects. Conclusion: The pharmacokinetics of dexamethasone in premature neonates was related to gestational age.     

A preliminary study of the pharmacodynamics and pharmacokinetics of a novel enkephalin analogue [Tyr-D.Arg-Gly-Phe(4NO2)·Pro·NH2 (BW443C)] in healthy volunteers

Summary We have studied 16 healthy men to evaluate preliminary pharmacodynamics and kinetics of BW443C given by i.v. infusions. Four volunteers received escalating doses at weekly intervals, starting at 0.1 µg·kg^–1 for 60 min and increasing to a maximum of 2.0 µg·kg^–1·min^–1 for 180 min. Subsequently 12 different subjects received single i.v. infusions of 10 µg·kg^–1·min^–1 for 20 min. Subjective effects were reported and objective measurements made of central nervous and cardiovascular effects. Blood was sampled at intervals on all occasions, plasma concentrations were determined by radioimmunoassay and pharmacokinetic profiles were analysed using NONLIN.Dry mouth and some nasal stuffiness were reported and postural hypotension occurred in 5/16 subjects at plasma concentrations >0.8 µg·ml^–1. Supine blood pressure was well maintained in all subjects and hypotension resolved within 60–90 min of discontinuing the infusion. There was no evidence of sedation, mood change, nausea, vomiting, miosis, change in accomodation or respiratory depression. Rapid infusions produced transient feelings of warmth, heavy eyelids, heavy legs, and increased bowel sounds, which resolved despite increasing plasma concentrations.The disposition of the peptide was adequately described by a 2-compartment model with a mean ± SD plasma clearance of 123±18 ml·min^–1 and a half-life of 2.0±0.4 h.     

The effect of a low dose of quinidine on the disposition of flecainide in healthy volunteers

Summary We have studied the effects of quinidine on ECG intervals and on the pharmacokinetics of flecainide and its two metabolites in 6 healthy men in an open randomized crossover study. Flecainide acetate (150 mg) was given as a constant rate i. v. infusion over 30 min.Quinidine (50 mg orally), given the previous evening, did not change the volume of distribution of flecainide (7.9 vs 7.41·kg^–1), but significantly increased its half-life (8.8 vs 10.7 h). This was attributable to a reduction in total clearance (10.6 vs 8.1 ml·min^–1·kg^–1), most of it being accounted for by a reduction in non-renal clearance (7.2 vs 5.2 ml·min^–1·kg^–1). The excretion of the metabolites of flecainide over 48 h was significantly reduced.These findings suggest that quinidine inhibits the first step of flecainide metabolism, although it may also reduce its renal clearance, but to a lesser extent (3.5 vs 2.9 ml·min^–1·kg^–1).The effects of flecainide on ECG intervals were not altered by quinidine.Thus, quinidine tends to shift extensive metabolizer status for flecainide towards poor metabolizer status and may also alter its renal excretion.     

Changes in muscle blood flow after smoking a cigarette determined by a new noninvasive method

Summary The pharmacokinetics of the H₂-receptor antagonist famotidine, after oral administration of a 20 mg tablet, has been studied in 10 elderly patients with normal renal function (CL_CR59 ml·min^–1, Mean=80 ml·min^–1), 5 elderly patients with renal insufficiency (CL_CR38 ml·min^–1, Mean=15 ml·min^–1), and 6 healthy young volunteers.Elimination half-life in the elderly patients with renal insufficiency was significantly prolonged compared to the elderly patients with normal renal function and the young volunteers. The correlation coefficient between creatinine clearance and the elimination rate constant of famotidine was 0.672. Mean urinary recovery of unchanged drug up to 24 h in the young volunteers was 44%. The mean renal clearance of famotidine in the young volunteers (270 ml·min^–1) was substantially greater than the creatinine clearance, 128 ml·min^–1, which suggests the possibility of tubular secretion of famotidine.     

Sex-difference and the effects of smoking and oral contraceptive steroids on the kinetics of diflunisal

Summary The single dose pharmacokinetics of diflunisal were studied in 4 groups of 6 young volunteers: control men, control women, women taking low estrogen oral contraceptive steroids (OCS), and women smokers (10–20 cigarettes/day).The plasma clearance of diflunisal was significantly higher in men (0.169 ml·min^–1·kg^–1) and in women on OCS (0.165 ml·min^–1·kg^–1) as compared to control women (0.108 ml·min^–1·kg^–1). Partial metabolic clearances of diflunisal by the three conjugative pathways (phenolic and acyl glucuronide formation, sulphate conjugation) were all increased in men and women OCS users as compared to control women. Statistically significant increases, however, were only observed for the partial metabolic clearance of diflunisal by phenolic glucuronidation between men and women (2.91 vs. 1.85 ml·min^–1 respectively), and for the partial clearance by acyl glucuronidation between OCS users and control women (4.81 vs. 3.01 ml·min^–1 respectively).Smoking resulted in a moderate increase (35%) in plasma diflunisal clearance. However, a significant reduction in total urinary recovery of diflunisal and its glucuronide and sulphate conjugates was found in smokers (70.5% in smokers as compared to 84.2–87.2% in the 3 other study groups). Consequently, smoking may have induced hydroxylation, a minor oxidative metabolic pathway of diflunisal recently discovered in man.     

Pharmacokinetics of baclofen in spastic patients receiving multiple oral doses

The pharmacokinetics of racemic baclofen as determined from plasma and urine data in six spastic patients treated with individualized oral doses, 30–80 mg daily, are presented. Peak plasma concentrations were achieved 1.9 h (±0.7) after a dose. The fluctuation in the plasma concentration was great, ranging from 188 to 439%. The total body clearance averaged 175 ml·min^–1 (±44), plasma protein binding 35% (±6). Baclofen was for the greater part excreted unchanged by the kidney, 65% (±16). Its apparent renal clearance equalled the creatinine clearance. The contribution of the renal clearance to the total body clearance can explain the previously described toxicity when renal impairment is present. The results agree with earlier reports on single doses in healthy subjects.     

Effect of loperamide on jejunal electrolyte and water transport,prostaglandin E 2-induced secretion and intestinal transit time in man

Summary Jejunal perfusion was performed in 12 healthy volunteers to evaluate the dose dependent effects of loperamide on intestinal absorption, stimulated secretion and transit.In 6 volunteers intestinal perfusion of the jejunal segment with isotonic NaCl solution was followed by addition of loperamide in increasing doses (2–8 mg·l^–1). The volunteers were pretreated with 1 mg·l^–1 prostaglandin E2 (PgE2) in the perfusate before addition of 4 mg·l^–1 loperamide. Phenolsulphonphtalein (PSP) boluses (2 ml) were given to measure mean transit time (MTT).Loperamide 2 mg·l^–1 converted the minor secretion after perfusion with the standard solution (water –1.45 ml·min^–1, Na –0.09 and Cl –0.04 mmol·min^–1) to absorption (water 0.93 ml·min^–1, Na 0.23, Cl 0.25 mmol·min^–1) within 15 min. Higher doses of loperamide did not increase absorption.The addition of PgE2 induced net secretion of water (–4.48 ml·min^–1) and electrolytes (Na –0.57, Cl –0.51 mmol·min^–1). Loperamide 4 mg·l^–1 significantly diminished the PgE2-induced net secretion by approximately 50%.Loperamide dose dependently increased the MTT from 6 (2 mg·l^–1) to 13.3 min (8 mg·l^–1). MTT was still delayed 60 min after a wash out period (10.5 min).It is concluded that loperamide had a dual effect or intestinal activities stimulating absorption and prolonging intestinal transit time with rising doses.     

The disposition and protein binding of batanopride and its metabolites in subjects with renal impairment

Summary We have studied the disposition of batanopride and its three major metabolites (the erythro-alcohol, threo-alcohol, and N-desethyl metabolites) in 27 subjects with various degrees of renal function after intravenous infusion of a single dose of 3.6·mg·kg^–1 of batanopride over 15 min.The subjects were assigned to one of three treatment groups: group 1, normal renal function (creatinine clearance 75 ml·min^–1·1.73 m^–2; n=13); group 2, moderate renal impairment (creatinine clearance 30–60 ml·min^–1·1.73 m^–2; n=8); group 3, severe renal impairment (creatinine clearance 30 ml·min^–1·1.73 m^–2; n=6).The terminal half-life of batanopride was significantly prolonged from 2.7 h in group 1 to 9.9 h in group 3. The renal clearance of batanopride was significantly lower in group 3 (25 ml·min^–1) compared with group 1 (132 ml·min^–1).There were no differences in plasma protein binding or steady-state volume of distribution of batanopride among the groups.There were significantly lower renal clearances for all three metabolites in groups 2 and 3 compared with group 1. The half-lives of all three metabolites were significantly prolonged in group 3 compared with group 1.The dose of batanopride may need to be reduced in patients with creatinine clearances less than 30 ml·min^–1·1.73 m^–2 to prevent drug accumulation and avoid possible dose-related adverse effects.     

Bioavailability and pharmacokinetics of oxazepam

Summary Six healthy volunteers received oxazepam 15 mg i.v. and orally at an interval of at least one week. The kinetic variables of i.v. oxazepam were: elimination half-life (t_1/2) 6.7 h, total clearance (CL) 1.07 ml·min^–1·kg^–1, volume of distribution (V_c) 0.27 l·kg^–1 (0.21–0.49) and volume of distribution at steady-state (V_ss) 0.59 l·kg^–1. The intravenous disposition of unbound oxazepam was characterized by a clearance of 22.5ml·min^–1·kg^–1 and a distribution volume of 12.3 l·kg^–1. After oral oxazepam the peak plasma level was reached in 1.7 to 2.8 h. The plasma t_1/2 at 5.8 h was not significantly different from the i.v. value. Absorption was almost complete, with a bioavailability of 92.8%. Urinary recovery was 80.0 and 71.4% of the dose after intravenous and oral administration, respectively. Renal clearance (CL_R) of the glucuronide metabolite was 1.10 ml·min^–1·kg^–1 (0.98–1.52). Oxazepam was extensively bound to plasma protein with a free fraction of 4.5%.