Midazolam metabolism

The metabolism of several CYP3A4 substrates in microsomes from the upper small intestine has been compared with liver microsomal metabolism. The results are summarized in Table 13.3. Thus, microsomes from the human upper small intestine can metabolize CYP3A4 substrates at rates approaching those found in human liver microsomes. However, the rate of metabolism in intestinal microsomes can be highly variable (8-fold for sirolimus [17] and 18- to 29-fold for midazolam [19]). 

This has been confirmed in activity studies where the rates of metabolism of midazolam [19] and erythromycin [14] have been studied in microsomes from... 

Tab. 13.4. Metabolism of midazolam and erythromycin in microsomes from human duodenum, jejunum and ileum.

Oral first-pass elimination of midazolam involves both gastrointestinal and hepatic CYP3A mediated metabolism, Clin. 

In vitro kinetic constants obtained from homogenate or whole-cell experiments under controlled conditions were used, and the constants were scaled to the in vivo scenario using appropriate physiological scale factors. Figure 18.6 shows our simulated results for absorption and metabolism of midazolam when dosed with and without grapefruit juice. Midazolam is metabolized by the gut and liver by cytochrome 3A4. Saquinavir is also metabolized in the gut and liver by 3A4, and it is also a substrate for efflux by P-gp. Figure 18.7 shows our simulated results for absorption and metabolism of saquinavir when dosed with and without grapefruit juice. In both cases, it can be seen that the simulation correctly predicts the... 

Besides catalyzing styrene and benzaldehyde, CYP enzymes play an important role in the metabolism of endogenous compounds as well as in pharmacokinetics and toxicokinetics. Joseph [228] developed a biosensor with human CYP3A4 as a novel drugscreening tool. It was constructed by assembling enzyme films on Au electrodes by alternate adsorption of a layer of CYP3A4 on top of a layer of PDDA. The biosensor was applied to detect verapamil, midazolam, quinidine, and progesterone. 

Yuan R, Flockhart DA, Balian JD Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam. J Clin Pharmacol 1999,39 1109-1125. 

Propofol is very lipid soluble, has a large volume of distribution, and has a rapid onset of action. It has comparable efficacy to midazolam for refractory GCSE. It has been associated with metabolic acidosis, hemodynamic instability, and bradyarrhythmias that are refractory to treatment. 

Paine MF, Shen DD, Kunze KL, Perkins JD, Marsh CL, Mcvicar JP, Barr DM, Gillies BS and Thummel KE (1996) First-Pass Metabolism of Midazolam by the Human Intestine. Clin Pharmacol Ther 60 pp 14—24. 

A complication of this can be additional first-pass effects caused by metabolism by the gastrointestinal tract itself In the most extreme cases, such as midazolam, extraction by the gut wall may be as high as 0.38 to 0.54 and comparable to that of the liver itself [9]. 

When considering the Hkely pharmacokinetic profile of a novel compound in man, it is important to recognize the variability that may be encountered in the cHnical setting. Animal pharmacokinetic studies are generally conducted in inbred animal colonies that tend to show minimal inter-subject variabiHty. The human population contains a diverse genetic mix, without the additional variability introduced by age, disease states, environmental factors and co-medications. Hence any estimate of pharmacokinetic behaviour in man must be tempered by the expected inherent variability. For compounds with high metabolic clearance (e. g. midazolam), inter-individual variability in metabolic clearance can lead to greater than 10-fold variation in oral clearance and hence systemic exposure [1]. 

Midazolam is a rapidly metabolized benzodiazepine (p. 228) that is used for induction of anesthesia. The longer-acting lorazepam is preferred as adjunct anesthetic in prolonged cardiac surgery with cardiopulmonary bypass its am-nesiogenic effect is pronounced. 

Do not administer concurrently with cisapride, midazolam, triazolam, or ergot derivatives. Competition for CYP3A4 by efavirenz could result in inhibition of metabolism of these drugs and create the potential for serious or life-threatening adverse events (eg, cardiac arrhythmias, prolonged sedation, respiratory depression see Drug Interactions). 

The importance of these enzymes for drug interactions is that enzyme inducers and inhibitors may preferentially affect certain isoforms and consequently may only affect the metabolism of selected drugs. For example, ketoconazole has the potential to inhibit the metabolism of drugs metabolised to a great extent by the sub-family 3A (e.g. midazolam) but not of those metabolised by sub-family 1A (e.g. theophylline), 2C (e.g. diazepam), or 2D (e.g. metaprolol). In contrast, although fluconazole is a weaker inhibitor of the sub-family 3A than ketoconazole, it also inhibits the sub-family 2C, and so the interactions of fluconazole differ from those of ketoconazole. 

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