The pharmacology of intravenous infusions of lorazepam differs significantly from that of midazolam in critically ill patients. This results in significant delays in emergence from sedation with lorazepam as compared with midazolam when administered for ICU sedation.

Emergence time from sedation with propofol in ICU patients varies with the depth of sedation, the duration of sedation, and the patient's body habitus. Maintaining a light level of sedation ensures a rapid emergence from sedation with long-term propofol administration.

Despite previous reports of high interindividual variability in midazolam pharmacodynamics in patients in the surgical intensive care unit, these cross-validation results suggest that, when midazolam is administered using a target-controlled infusion device, the level of sedation can be predicted within 1 sedation score in 88% of patients based on the target midazolam concentration and the time since the conclusion of the anesthetic.

The intersubject variability and predictability of the three-compartment pharmacokinetic model are similar to those of other intravenous anesthetic drugs. This multicenter study did not confirm previous studies of exceptionally large variability of midazolam pharmacokinetics when used for sedation in intensive care settings.

1. The rates of diazepam (DZ) metabolism to the primary metabolites 3-hydroxydiazepam, 4'-hydroxydiazepam and nordiazepam were studied in vitro using rat hepatic microsomes and hepatocytes. 4'-hydroxydiazepam had the largest intrinsic clearance (Vmax/Km ratio, CL(int)) in both microsomes and hepatocytes representing 49 and 70% of total metabolism respectively. Whereas the contribution of 3-hydroxydiazepam was similar in both systems (21-24%), the N-demethylation pathway was greater in microsomes (27%) than hepatocytes (9%). 2. The pharmacokinetics of DZ were determined in vivo using the intraportal route to avoid blood flow limitations due to the high clearance of DZ. No dose dependency was observed in either clearance or steady state volume of distribution, which were estimated to be 38 ml/min/SRW (where SRW is a standard rat weight of 250 g) and 1.3 L/SRW respectively. Blood binding of DZ was concentration independent, the unbound fraction being 0.22. 3. Scaling factors were used to relate the in vitro CL(int) to the in vivo unbound clearance. Hepatocytes (123 ml/min/SRW) produced a more realistic prediction for the in vivo value (174 ml/min/SRW) than microsomes (41 ml/min/SRW). This situation is believed to arise from the quantitative differences in the three metabolic pathways in the two in vitro systems. It is speculated that end product inhibition is responsible for reduced total metabolism in microsomes whereas hepatocytes operate kinetically in a manner close to in vivo.

The amount of fentanyl absorbed from the PCTS increases as a function of time and is independent of both dosing frequency and total number of doses delivered. The fentanyl HCl PCTS is generally safe and well tolerated.

1. The potency and selectivity of omeprazole as an inhibitor of cytochrome P450-mediated drug oxidations has been assessed in hepatic microsomes from the untreated, phenobarbitone-treated, beta-naphthoflavone-treated and dexamethasone-treated rat. Using the marker substrates diazepam, ethoxycoumarin, ethoxyresofurin and ethylmorphine in the above microsomal preparations, inhibitory activity against CYP1A, 2B, 2C and 3A members of the cytochrome P450 superfamily were determined. 2. In each situation studied the kinetics of inhibition by omeprazole were competitive in nature with Ki's ranging from 25 to > 1000 microM. Marker activities for the 3A family in microsomes from the dexamethasone-treated and phenobarbitone-treated rat (3-hydroxylation of diazepam and N-demethylation of ethylmorphine) were most susceptible to omeprazole inhibition (Km/Ki ratios greater than unity) compared with marker activities for the CYP1A, 2B and 2C sub-families (Km/Ki ratios < or = unity). 3. Omeprazole sulphoxide showed similar potency and selectivity of inhibition to its parent drug. Analogous studies with the same marker activities using ketoconazole indicated that both omeprazole and its sulphoxide metabolite are less potent as an inhibitor of cytochrome P4503A in rat than this well characterised prototype.

1 The metabolism of diazepam to its primary metabolites 3-hydroxydiazepam (3HDZ) and nordiazepam ( NDZ) was evaluated in human liver microsomes. The 3HDZ pathway was the major route of metabolism representing 90% of total metabolism with a V max /K m ratio of 0.50-7.26 ml min−1 mg−1 protein. 2 Inhibition of the two metabolic pathways of diazepam by omeprazole was investigated. The NDZ pathway was not affected by omeprazole whilst a K i of 201±89 m was obtained for the 3HDZ pathway (K m /K i ratio of 3.0±0.9). 3 Inhibitory effects of omeprazole sulphone on the 3HDZ and NDZ pathways were also investigated. Omeprazole sulphone inhibited both pathways with similar K i s of 121±45 and 188±73 m respectively (K m /K i ratios of 5.2±2.3 and 3.3±1.5 respectively). 4 These in vitro data provide direct evidence for cytochrome P450 inhibition as the mechanism for the well documented diazepam-omeprazole clinical interaction and indicate that omeprazole sulphone, as well as the parent drug, contribute to the inhibition effect.Keywords omeprazole diazepam omeprazole sulphone human microsomes in vitro metabolism drug interactions CYP3A CYP2C19