Simultaneous pharmacokinetics evaluation of human cytochrome P450 probes,caffeine, warfarin,omeprazole, metoprolol and midazolam,in common marmosets (Callithrix jacchus)

1.?Pharmacokinetics of human cytochrome P450 probes (caffeine, racemic warfarin, omeprazole, metoprolol and midazolam) composite, after single intravenous and oral administrations at doses of 0.20 and 1.0?mg?kg^?1, respectively, to four male common marmosets were investigated.

2.?The plasma concentrations of caffeine and warfarin decreased slowly in a monophasic manner but those of omeprazole, metoprolol and midazolam decreased extensively after intravenous and oral administrations, in a manner that approximated those as reported for pharmacokinetics in humans.

3.?Bioavailabilities were ～100% for caffeine and warfarin, but <25% for omeprazole and metoprolol. Bioavailability of midazolam was 4% in marmosets, presumably because of contribution of marmoset P450 3A4 expressed in small intestine and liver, with a high catalytic efficiency for midazolam 1′-hydroxylation as evident in the recombinant system.

4.?These results suggest that common marmosets, despite their rapid clearance of some human P450 probe substrates, could be an experimental model for humans and that marmoset P450s have functional characteristics that differ from those of human and/or cynomolgus monkey P450s in some aspects, indicating their importance in modeling in P450-dependent drug metabolism studies in marmosets and of further studies.     

Effect of kanglaite on rat cytochrome P450

Abstract

Context: Kanglaite (KLT) is an oily substance extracted from Coix lacryma-jobi Linn. (Cramineae) and has been proved to significantly improve the life span and quality of life of patients, when combined with chemotherapy, radiotherapy, or surgery.

Objective: The purpose of this study was to find out whether KLT influences the effect on rat cytochrome P450 (CYP) enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4) by using cocktail probe drugs in vivo.

Materials and methods: A cocktail solution at a dose of 5?mL/kg, which contained phenacetin (20?mg/kg), bupropion (20?mg/kg), tolbutamide (5?mg/kg), omeprazole (20?mg/kg), and midazolam (10?mg/kg), was given as oral administration to rats treated with 7?d intraperitoneal injection of KLT. Blood samples were collected at a series of time-points and the concentrations of probe drugs in plasma were determined by HPLC-MS/MS. The corresponding pharmacokinetic parameters were calculated by the software of DAS 2.0 (SPPS Inc., Chicago, IL).

Results: In the experiment, there was a statistically significant difference in the t_1/2, C_max, AUC_(0–∞), and CL for phenacetin, bupropion, tolbutamide, omeprazole, and midazolam. Our study showed that treatment with multiple doses of KLT had induction effect on rat CYP1A2, while CYP2B6, CYP2C9, CYP2C19, and CYP3A4 enzyme activities had been inhibited after multiple doses of KLT treatment.

Conclusions: KLT can either induce or inhibit activities of CYP. Therefore, caution is needed when KLT is co-administration with some CYP substrates in clinic, which may result in herb–drug interactions.     

Mechanism-based inhibition of human cytochrome P4503A4 by domperidone

1. Domperidone was evaluated in direct and time-dependent cytochrome P450 (CYP) 3A inhibition assays in human liver microsomes with midazolam and testosterone as probe substrates.

2. Domperidone was found to be a modest mechanism-based inhibitor of human and rat CYP3A. For human CYP3A, the inactivation constant (K_I) is 12 μM, and the maximum inactivation rate (k_inact) is 0.037?min^?1.

3. A rat interaction study was conducted between midazolam and either a single dose or five daily doses of domperidone. Although a single oral dose of 10?mg kg^?1 domperidone did not affect the pharmacokinetics of 10?mg kg^?1 oral midazolam, five daily oral doses of domperidone almost doubled the area under the plasma concentration versus time curve (AUC) of midazolam, and increased the maximum plasma concentration (C_max) of midazolam by 72%.

4. Based on the simulation and rat in vitro–in vivo extrapolation, it is predicted that co-administration of domperidone in humans could modestly increase (approximately 50%) the exposure of drugs that are primarily cleared by CYP3A.

     

Model for the drug–drug interaction responsible for CYP3A enzyme inhibition. II: establishment and evaluation of dexamethasone-pretreated female rats

1.?Cytochrome P450 (CYP) 3A catalysis of testosterone 6β-hydroxylation in female rat liver microsomes was significantly induced, then reached a plateau level after pretreatment with 80?mg?kg^?1?day^?1 dexamethasone (DEX) for 3 days.

2.?Midazolam was mainly metabolized by CYP3A in DEX-treated female rat liver microsomes from an immuno-inhibition study, and the apparent K_m was 1.8?μM, similar to that in human microsomes.

3.?Ketoconazole and erythromycin, typical CYP3A inhibitors, demonstrated extensive inhibition of midazolam metabolism in DEX-treated female rat liver microsomes, and the apparent K_i values were 0.088 and 91.2?μM, respectively. The values were similar to those in humans, suggesting that DEX-treated female rat liver microsomes have properties similar to those of humans.

4.?After oral administration of midazolam, the plasma midazolam concentration in DEX-treated female rats significantly decreased compared with control female rats. The area under the plasma concentration curve (AUC) and elimination half-life were one-11th and one-20th of those of control female rats, respectively.

5.?Using DEX-treated female rats, the effect of CYP3A inhibitors on midazolam pharmacokinetics was evaluated. The AUC and maximum concentration in plasma (C_max) increased when ketoconazole was co-administered with midazolam.

6.?It was shown that the drug–drug interaction that occurs in vitro is also observed in vivo after oral administration of midazolam. In conclusion, the DEX-treated female rat could be a useful model for evaluating drug–drug interactions based on CYP3A enzyme inhibition.     

Oral Single Doses of Erythromycin and Roxithromycin May Increase the Effects of Midazolam on Human Performance

Macrolide antibiotics are known to inhibit the metabolism of triazolam and midazolam in vitro and in vivo. To find out if significant interactions take place after single oral doses of these agents to man, 0.25 mg triazolam and 5, 10 and 15 mg of midazolam in capsule form were given with and without 750 mg erythromycin or 300 mg roxithromycin to parallel groups of healthy subjects in four placebo-controlled double-blind studies. Objective tests and subjective assessments were made before the intake of hypnotics and 30 and 90 min after it. In Study I, triazolam impaired letter cancellation, the combination triazolam + erythromycin impaired digit symbol substitution and letter cancellation, and triazolam + roxithromycin impaired digit symbol substitution, all at 90 min. In Study II, midazolam 5 mg and midazolam 10 mg proved quite inert but the combination midazolam 5 mg + erythromycin impaired digit symbol substitution. In Study III, both midazolam 10 mg and midazolam 15 mg impaired digit substitution and letter cancellation, the effects of 15 mg being more prominent. The strongest drug effects were found with midazolam 10 mg + erythromycin which differed from placebo and midazolam (10 mg and 15 mg) in several objective and subjective test variables. In Study IV, the combination midazolam 10 mg + roxithromycin impaired several objective and subjective variables but it was not stronger than midazolam 15 mg. These results were supported by the direct measurements of plasma midazolam in three subjects: erythromycin increased plasma midazolam more than roxithromycin and enhanced midazolam effects following the intake of midazolam 10 mg. Our results suggest that sedation produced by hypnotic doses of midazolam is enhanced by erythromycin and perhaps by roxithromycin after single oral doses. The combined effects of triazolam together with erythromycin and roxithromycin were unclear, partly due to the relatively lower dose of triazolam.     

The effect of midazolam administration on the pharmacokinetics of antipyrine in the rat

1. The clearance and elimination half-lives for i.v. doses of antipyrine were determined in 6 groups of 6 male CD rats with no prior treatment, then again following 7 days treatment with graded oral doses of midazolam, and finally after 3 i.p. doses of phenobarbitone.

2. Substantial increases in clearance and decreases in half-lives were observed following phenobarbitone treatment, demonstrating that antipyrine provides a reliable index of enzyme induction.

3. After treatment with midazolam, maximal induction was seen in animals dosed at 27 or 80 mg/kg per day; an intermediate effect was found with 9 mg/kg per day and no effect at 0.2 and 1.0 mg/kg per day.

4. The results indicate that there is a substantial margin of safety between the proposed human therapeutic doses (7.5 to 15 mg/day) and the minimum effective dose that leads to enzyme induction in laboratory animals.     

Effects of aging and rifampicin pretreatment on the pharmacokinetics of human cytochrome P450 probes caffeine,warfarin, omeprazole,metoprolol and midazolam in common marmosets genotyped for cytochrome P450 2C19

1. The pharmacokinetics were investigated for human cytochrome P450 probes after single intravenous and oral administrations of 0.20 and 1.0?mg/kg, respectively, of caffeine, warfarin, omeprazole, metoprolol and midazolam to aged (10–14?years old, n?=?4) or rifampicin-treated/young (3?years old, n?=?3) male common marmosets all genotyped as heterozygous for a cytochrome P450 2C19 variant.

2. Slopes of the plasma concentration–time curves after intravenous administration of warfarin and midazolam were slightly, but significantly (two-way analysis of variance), decreased in aged marmosets compared with young marmosets. The mean hepatic clearances determined by in silico fitting for individual pharmacokinetic models of warfarin and midazolam in the aged group were, respectively, 23% and 56% smaller than those for the young group.

3. Significantly enhanced plasma clearances of caffeine, warfarin, omeprazole and midazolam were evident in young marmosets pretreated with rifampicin (25?mg/kg daily for 4?days). Two- to three-fold increases in hepatic intrinsic clearance values were observed in the individual pharmacokinetic models.

4. The in vivo dispositions of multiple simultaneously administered drugs in old, young and P450-enzyme-induced marmosets were elucidated. The results suggest that common marmosets could be experimental models for aged, induced or polymorphic P450 enzymes in P450-dependent drug metabolism studies.     

Impact of nonlinear midazolam pharmacokinetics on the magnitude of the midazolam-ketoconazole interaction in rats

1. Numerous groups have described the rat as an in vivo model for the assessment and prediction of drug–drug interactions (DDIs) in humans involving the inhibition of cytochrome P450 3A forms. Even for a well-established substrate-inhibitor pair like midazolam-ketoconazole, however, the magnitude of the DDI in rats (e.g. 1.5- to 5-fold) does not relate to what is observed clinically (e.g. 5- to 16-fold).

2. Because nonlinear substrate pharmacokinetics (PK) may result in a weaker interaction, it was hypothesized that the lower magnitude of interaction observed in rats was due to the saturation of metabolic pathway(s) of midazolam at the doses used (10–20 mg/kg). Therefore, the inhibitory effects of ketoconazole were reevaluated at lower oral (1 and 5 mg/kg) and intravenous (IV) (1 mg/kg) doses of midazolam.

3. In support of the hypothesis, oral exposure at 5 mg/kg dose of midazolam was 18-fold higher compared to that at 1 mg/kg. Furthermore, when the interaction was investigated at the lower midazolam dose (1 mg/kg), ketoconazole increased the IV and oral exposure of midazolam by 7-fold and 11-fold, respectively. A weaker DDI (1.5- to 1.8-fold) was observed at the higher oral midazolam dose.

4. Collectively, these results suggest that the lower reported interaction in rats is likely due to saturation of midazolam clearance at the doses used. Therefore, when the rat is used as a DDI model to screen and differentiate compounds, or predict CYP3A inhibition in humans, it is important to use low doses of midazolam and ensure linear PK.

     

Gamma-hydroxybutyrate: is it a feasible alternative to midazolam in long-term mechanically ventilated children?

Aim: Benzodiazepines like midazolam are commonly used for long-term sedation of critically ill children requiring mechanical ventilation. Tolerance to midazolam may occur in these patients resulting in a ceiling effect with insufficient or missing sedative response to increases of midazolam infusion or bolus application. The aim of this study was to evaluate the feasibility of a drug rotation protocol replacing continuous infusion of midazolam with gamma-hydroxybutyrate (GHB) to counteract midazolam tolerance.

Methods: This retrospective, observational study was conducted in a 14-bed pediatric intensive care unit of a tertiary referral center. Thirty-three mechanically ventilated children with tolerance to midazolam who received continuous infusion of GHB were included. Success of drug rotation from midazolam to GHB was defined as adequate sedation with GHB and subsequent reduction of required doses of midazolam.

Results: In our cohort, drug rotation for at least 2?days could be successfully performed in 10 out of 34 children resulting in subsequent reduction of required doses of midazolam. Drug rotation to GHB failed in 24 patients due to insufficient sedation resulting in a premature termination of the protocol. In these children, dosing of midazolam could not be reduced following drug rotation. We could not identify factors which predict success or failure of drug rotation from midazolam to GHB.

Conclusions: The data from our single-center study suggest that drug rotation from midazolam to GHB may be worth trying in children with midazolam tolerance during long-term sedation, but physicians should be aware of possible treatment failure.     

Pharmacokinetics of intravenous and oral midazolam in plasma and saliva in humans: usefulness of saliva as matrix for CYP3A phenotyping

AIMS

To compare midazolam kinetics between plasma and saliva and to find out whether saliva is suitable for CYP3A phenotyping.

METHODS

This was a two way cross-over study in eight subjects treated with 2 mg midazolam IV or 7.5 mg orally under basal conditions and after CYP3A induction with rifampicin.

RESULTS

Under basal conditions and IV administration, midazolam and 1′-hydroxymidazolam (plasma, saliva), 4-hydroxymidazolam and 1′-hydroxymidazolam-glucuronide (plasma) were detectable. After rifampicin, the AUC of midazolam [mean differences plasma 53.7 (95% CI 4.6, 102.9) and saliva 0.83 (95% CI 0.52, 1.14) ng ml⁻¹ h] and 1′-hydroxymidazolam [mean difference plasma 11.8 (95% CI 7.9, 15.7) ng ml⁻¹ h] had decreased significantly. There was a significant correlation between the midazolam concentrations in plasma and saliva (basal conditions: r = 0.864, P < 0.0001; after rifampicin: r = 0.842, P < 0.0001). After oral administration and basal conditions, midazolam, 1′-hydroxymidazolam and 4-hydroxymidazolam were detectable in plasma and saliva. After treatment with rifampicin, the AUC of midazolam [mean difference plasma 104.5 (95% CI 74.1, 134.9) ng ml⁻¹ h] and 1′-hydroxymidazolam [mean differences plasma 51.9 (95% CI 34.8, 69.1) and saliva 2.3 (95% CI 1.9, 2.7) ng ml⁻¹ h] had decreased significantly. The parameters separating best between basal conditions and post-rifampicin were: (1′-hydroxymidazolam + 1′-hydroxymidazolam-glucuronide)/midazolam at 20–30 min (plasma) and the AUC of midazolam (saliva) after IV, and the AUC of midazolam (plasma) and of 1′-hydroxymidazolam (plasma and saliva) after oral administration.

CONCLUSIONS

Saliva appears to be a suitable matrix for non-invasive CYP3A phenotyping using midazolam as a probe drug, but sensitive analytical methods are required.

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT

• Midazolam is a frequently used probe drug for CYP3A phenotyping in plasma. Midazolam and its hydroxy-metabolites can be detected in saliva.

WHAT THIS STUDY ADDS

• The concentrations of midazolam and its hydroxy-metabolites are much lower in saliva than in plasma, but the midazolam concentrations in both matrices show a significant linear correlation.
• Saliva appears to be a suitable matrix for CYP3A phenotyping with midazolam, but very sensitive methods are required due to the low concentrations of midazolam and its hydroxy-metabolites.

     

Multiple intragastric treatment versus continuous administration via the diet. Comparative pharmacokinetics of abecarnil in mouse

1. Abecarnil was administered to female mice at doses of 5, 50 and 150 mg/kg per day for 4 weeks either intragastrically once a day or was offered continuously via the diet.

2. On days 1, 7, 14 and 28 plasma level profiles (0-24h) were determined in identical groups of animals. Additionally, faecal excretion of abecarnil and distribution in brain, liver and kidney was measured.

3. Drug administration via the diet was characterized by

(a) a circadian rhythm of concentrations with highs at night and lows during the day;

(b) a dose-proportional increase in AUC and mean plasma levels;

(c) slight accumulation in the plasma after the two higher doses.

4. Intragastric treatment resulted in

(a) clearly distinguishable absorption and disposition phases in the plasma with prominent peaks;

(b) slight accumulation at the two higher doses;

(c) dose-proportionality for the 50 and 150 mg/kg doses.

5. Drug load after the two routes of administration was different resulting in four times higher peak plasma levels and in double AUC values after intragastric administration than after the diet.     

Pharmacokinetics and pharmacodynamics of low doses of midazolam administered intravenously and orally to healthy volunteers

1. Midazolam, a short‐acting benzodiazepine, has been considered a probe for estimating hepatic and intestinal cytochrome P450 (CYP) 3A activity in humans. The aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of midazolam administered intravenously (i.v.) and orally (p.o.) at relatively low doses to healthy volunteers. 2. The present study was an open‐label, single‐sequence trial in three phases distinguished by differing doses of midazolam. Plasma concentrations of midazolam and its metabolites, as well as pharmacodynamic parameters, were measured simultaneously after administration of 5, 15 and 30 μg/kg, i.v., midazolam and 15, 50 and 100 μg/kg, p.o., midazolam. 3. The area under the concentration–time curve (AUC) of midazolam was significantly correlated with dose after both i.v. and oral administration (both P < 0.001). The AUC_0–6 of midazolam after oral administration was also well correlated with the area under the effect curve for peak saccadic velocity (PSV; P < 0.018), postural sway area (PSA; P < 0.069) and mental sedation as measured on a visual analogue scale (VAS; P < 0.054), but not for critical flicker fusion. 4. The present study has shown that the pharmacokinetics of midazolam at relatively low doses are linear for both intravenous and oral dosing regimens. In addition, PSV, PSA and VAS may be useful for the simultaneous evaluation of the pharmacokinetics and pharmacodynamics of midazolam at subtherapeutic doses.     

Model for the drug–drug interaction responsible for CYP3A enzyme inhibition. I: evaluation of cynomolgus monkeys as surrogates for humans

1.?Anti-human cytochrome P450 (CYP) 3A4 antiserum completely inhibited midazolam metabolism in monkey liver microsomes, suggesting that midazolam was mainly metabolized by CYP3A enzyme(s) in monkey liver microsomes.

2.?Midazolam metabolism was also inhibited in vitro by typical chemical inhibitors of CYP3A, such as ketoconazole, erythromycin and diltiazem, and the apparent K_i values for ketoconazole, erythromycin and diltiazem were 0.127, 94.2 and 29.6?μM, respectively.

3.?CYP3A inhibitors increased plasma midazolam concentrations when midazolam and CYP3A inhibitors were co-administered orally. However, the pharmacokinetic parameters of midazolam were not changed by treatment with CYP3A inhibitors when midazolam was given intravenously. This suggests that CYP3A inhibitors modified the first-pass metabolism in the liver and/or intestine, but not systemic metabolism.

4.?The drug–drug interaction responsible for CYP3A enzyme(s) inhibition was observed when midazolam and inhibitors were co-administrated orally. Therefore, it was concluded that monkeys given midazolam orally could be useful models for predicting drug–drug interactions in man based on CYP3A enzyme inhibition.     

Metabolism of isoprenaline in dog and man

1. The metabolism of isoprenaline has been studied in man and dog following intravenous and oral or intra-duodenal administration.

2. Intravenous isoprenaline was excreted largely unchanged in urine in both species. Only one-third of the radioactivity in urine was in the form of the O-methyl metabolite.

3. After oral doses in man or intraduodenal doses in dogs, plasma radioactivity was almost entirely as conjugated isoprenaline and this metabolite accounted for more than 80% of radioactivity in urine.

4. Catechol-O-methyl transferase may be less important than Uptake₂ in limiting the pharmacological action of isoprenaline.

5. Pharmacological response (heart-rate increase) was related to plasma concentration of isoprenaline only after rapid intravenous injections. In dogs, following prolonged infusion or intraduodenal doses, heart rate returned to base-line values when plasma concentrations of isoprenaline were high.

     

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%).     

Acute effects of varying doses of propranolol upon oxygen haemoglobin affinity in man

1 The effect of propranolol 2 h following doses of 10, 30, or 100 mg upon the blood oxygen-haemoglobin dissociation curves has been studied in four normal subjects.

2 The pO₂ at 50% saturation (p50) was not changed significantly under control conditions or after 10 and 100 mg doses. There was a just significant increase of 2 mmHg in the p50 value after the 30 mg dose.

3 There was no significant change in red cell adenosine triphosphate or 2,3-diphosphoglycerate nor in plasma phosphate.

4 There was no correlation between plasma propranolol concentration and changes in blood p50.

     

Pharmacokinetics and metabolism of midazolam in chimeric mice with humanised livers

1. The pharmacokinetics and biotransformation of midazolam were investigated following single oral doses of 0.1, 1 and 10 mg/kg to chimeric mice with humanised livers (PXB mice) and to severe combined immunodeficient (SCID) mice used as controls.

2. Pharmacokinetic analysis, on whole blood, revealed rapid absorption of the administered midazolam with a higher C_max in PXB compared to SCID. The exposure to 1′-hydroxymidazolam was approximately 14-fold greater than to midazolam in the SCID mice and close to equivalent in the PXB mice. The metabolism of midazolam in SCID mice was faster than in the PXB mice such that pharmacokinetic data for midazolam in SCID mice could not be generated from the lowest dose in these animals.

3. Both oxidative and conjugative metabolic pathways were identified in the PXB mice. All the major circulating metabolites observed in humans; 1′-hydroxymidazolam, 4′-hydroxymidazolam, 1′,4′-dihydroxymidazolam and 1′-hydroxymidazolam glucuronide, were detected in the blood of PXB mice. However, 4′-hydroxymidazolam and the 1′-hydroxymidazolam glucuronide were not detected in blood samples obtained from SCID mice.

4. The midazolam metabolite profile in the PXB mouse was similar to that previously reported for human suggesting that the PXB mouse model can provide a model system for predicting circulating human metabolites.

     

Integrated pharmacokinetics and pharmacodynamics of Ro 48–6791, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects

Aims This study was performed to investigate the pharmacokinetics and pharmacodynamics of ascending doses of Ro 48–6791, compared with midazolam, in healthy subjects during first administration to man studies. Methods The study was double-blind and five-way crossover with treatment on 5 consecutive days (three ascending doses, placebo, fixed midazolam dose) in two sequential groups of five healthy male subjects. Ro 48–6791 was administered as a slow i.v. infusion in doses of 0.1–0.3–1 mg in the first group, and 1–2–3 mg in the second. Midazolam was infused at 0.1 mg kg⁻¹. The infusions were stopped after 20 min or if sedation became too strong for proper performance of the tests. Consequently, infusion rates (mg min⁻¹ ) differed considerably among doses. Blood samples were collected frequently for pharmacokinetic determinations (two-compartment model). Pharmacodynamics were assessed by recording of saccadic eye movements (saccadic peak velocity) and electroencephalography (&bgr;-power). These parameters were used for pharmacokinetic/pharmacodynamic modelling. Results Ro 48–6791 and midazolam were both well tolerated. Most clinical events were dose-dependent central depressant effects. The volume of distribution (V_ss ) and plasma clearance of Ro 48–6791 were on average markedly larger than those of midazolam (171±65 vs 41±10 l and 2.2±0.9 vs 0.42±0.11 l min⁻¹, respectively). The doses of Ro 48–6791 leading to loss of saccadic eye movements were on average four times lower than that of midazolam. The corresponding predicted effect compartment concentrations differed by a factor of about six. Doses of Ro 48–6791 and midazolam eliciting similar maximum effects had a comparable onset and duration of action for saccadic peak velocity. Midazolam caused a significantly larger (33%, range 17, 55%) increase in &bgr;-power than Ro 48–6791 at the highest administered dose. Ro 48–6792, a metabolite of Ro 48–6791, showed a considerably longer half-life than the parent compound. Although there were no indications of a discernable effect of Ro 48–6792 in the present study, the effects of possible accumulation during prolonged administration should be investigated further. Conclusions This first study with Ro 48–6791 in humans has shown that this benzodiazepine is approximately four to six times as potent as midazolam, but has a comparable onset and duration of action.     

Respiratory and cardiovascular effects in relation to plasma levels of midazolam and diazepam.

1. In the present study possible relationships between cardiovascular and respiratory effects and plasma concentrations were investigated after administration of midazolam and diazepam. Eight healthy volunteers were given three injections at 20 min intervals of equipotent sedative doses of midazolam (0.05 mg kg-1) and diazepam (0.15 mg kg-1) in a randomized double-blind cross-over design. Blood pressure, blood-gases and respiration measured nonivasively, were monitored throughout the experimental session of 160 min, and frequent blood samples were collected during the session. 2. Correlations between the blood pressure reduction, the increase of PaCO2 in blood, and plasma concentrations were found for both drugs. A maximal reduction of blood pressure and PaCO2 was produced after sedative doses of midazolam and diazepam. 3. A possible acute tolerance development towards the blood pressure reduction was found after the repeated administration of diazepam but not after the midazolam administration. 4. The plasma concentrations producing half the maximal effects after administration of midazolam was 50-60 ng ml-1, indicating that the influence on blood pressure and PaCO2 after drug administration is evoked at lower plasma concentrations than sedation. 5. No correlation between the respiratory effects and plasma concentrations was found for either drug.     

Dose dependent pharmacokinetics of midazolam

Summary The pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were investigated following oral administration of 7.5, 15 and 30 mg doses of midazolam in solution to 12 healthy subjects. Compared to the 7.5 mg dose, the C_max and AUC parameters of both midazolam and 1-hydroxymethylmidazolam increased proportionally after the 15 mg dose and more than proportionally after the 30 mg dose. The t_1/2 for midazolam remained relatively constant between the 7.5 and 15 mg doses whereas it increased slightly but significantly after the 30 mg dose. These data indicated that the pharmacokinetics of midazolam and 1-hydroxymethylmidazolam were linear between the 7.5 and 15 mg oral dose range. However, after the 30 mg dose, the systemic availability of midazolam and the AUC for 1-hydroxymethylmidazolam appeared to be greater than that anticipated from the lower doses, possibly due to saturation of midazolam first-pass metabolism. This ist not expected to have any clinical significance under the conditions of therapeutic use.