Midazolam pharmacokinetics

Merry C, Mulcahy F, Barry M, Gibbons S, Back D. Saquinavir interaction with midazolam pharmacokinetic considerations when prescribing protease inhibitors for patients with HIV disease (letter). AIDS 1997 11 268-9. 

Hokin-Neaverson M, Burckhardt WA, Jefferson JW Increased erythrocyte Na" pump and Na-K-ATPase activity during lithium therapy. Research Communications in Chemical Pathology and Pharmacology 14 117-126, 1976 Holazo AA, Winkler MB, Patel IH Effects of age, gender and oral contraceptives on intramuscular midazolam pharmacokinetics. J Clin Pharmacol 28 1040-1045, 1988... 

CYP3A4 and CYP3A5 genotyping tests could not explain sufficiently the inter-individual variability observed in midazolam pharmacokinetics (Eap 2004). 

Nakajima M, Suzuki T, Sasaki T, Yokoi T, Hosoyamada A, Yamamoto T, Kuroiwa Y. Effects of chronic administration of glucocorticoid on midazolam pharmacokinetics in humans. Ther Drug Monit 1999 21(5) 507-13. 

Holazo AA, Winkler MB, Patel IH. Effects of age, gender and oral contraceptives on intramuscular midazolam pharmacokinetics. J Clin Pharmacol 1988 28 1040-5. 

For drugs examined in this exercise, the phenotypic measure of induction is CYP3A4 activity and since these responses are estimated by various techniques (midazolam pharmacokinetics, erythromycin breath test), it is difficult to relate the... 

Atomoxetine did not aiter desipramine pharmacokinetics and wouid therefore not be expected to affect other substrates of CYP2D6. Atomoxetine did not aiter midazolam pharmacokinetics and wouid therefore not be expected to affect other substrates of CYP3A4. Antacids and omeprazole do not alter atomoxetine bioavaiiabiiity. 

Lam YWF, Alfaro CL, Ereshefsky L, Miller M. Effect of antidepressants and ketoconazole on oral midazolam pharmacokinetics. Clin Pharmacol Ther( 99S) 63,229. 

The in vivo consequences of 3A5 polymorphism are not clear. For instance, Huang found no significant effect of the 3 polymorphism on midazolam pharmacokinetics [1476]. 

At this point, the significance of the wide variability in P450 3A5 is still difficult to assess. As mentioned previously, Huang [1476] found no significant effect of the 3 allele on midazolam pharmacokinetics in Chinese individuals. However, it is possible that the extrahepatic expression [1253] may influence the course of particular drags and other chemicals. 

Paediatrics Circadian rhythms was assessed during prolonged midazolam infusion in 27 paediatric intensive care unit children under mechanical ventilation [13 ]. This study foxmd that endogenous rhythms in critically ill and sedated children are severely disturbed and desynchronised. It also suggested that midazolam pharmacokinetics were not influenced by the light-dark cycle in children in intensive care xmits (ICUs). 

Bjorkman S, Wada DR, Berling BM, Benoni G. Prediction of the disposition of midazolam in surgical patients by a physiologically based pharmacokinetic model. J Pharm Sci 2001 Sep 90(9) 1226-41. 

Zhang, W. et al.. Impact of curcnmin-induced changes in P-glycoprotein and CYP3A expression on the pharmacokinetics of peroral cehprolol and midazolam in rats. Drug Metab. Dispos., 35, 110, 2007. 

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. 

R. J. Henry, N. Ruano, D. Casto, and R. H. Wolf. A pharmacokinetic study of midazolam in dogs Nasal drop vs. atomizer administration. Pediatr Dent 20 321-326 (1998). 

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]. 

Several studies have suggested increased sensitivity of older persons to effects of benzodiazepines (Table 3). For example, midazolam, widely used for rapid sedation for procedures, requires lower doses to reach defined end points of sedation that is attributable to a 59% reduction in the EC50 (the concentration that produces 50% of the maximum effect) and not to changes in pharmacokinetics, as shown in Fig. 3. The reasons for this increased sensitivity are not known. Animal studies have not shown any difference in brain benzodiazepine receptor density or affinity or effects on the associated chloride channel function with ageing. In any event, benzodiazepine doses should be reduced in older patients. 

Albrecht S, Ihmsen H, Hering W, Geisslinger G, Dinge-manse J, Schwilden H et al. The effect of age on the pharmacokinetics and pharmacodynamics of midazolam. Clin Pharmacol Ther 1999 65(6) 630-9. 

Tobacco and rifampin both induce hepatic enzymes, which may decrease the duration of action of the BZs. Grapefruit juice has received recent recognition as a factor in the pharmacokinetics of many drugs. Grapefruit juice slows down the GI absorption of midazolam and also decreases biotransformation, which leads to a delayed onset of effect and an increase in drowsiness (Ameer and Weintraub, 1997). 

Greenblatt DJ, Ehrenberg BL, Gunderman JS, et al. Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam and placebo. Clin Pharmacol Ther 1989 45(4) 356-365. 

Alprazolam did not exhibit any changes in pharmacokinetic parameters when administered concomitantly with GFJ (130) in a single dose experiment. When predosing existed, GFJ increased the exposure of alprazolam only in smokers. However, this interaction seems unlikely to be clinically relevant. In both parts of this study psychomotor fimction remained unchanged however, there was a small decrease in cognitive speed in the single dose part at one and two hours after dosing. Midazolam (6,15,133,134) and triazolam... 

Lam, Y.W., Alfaro, C.L., Ereshefsky, L., and Miller, M., Pharmacokinetic and pharmacodynamic interactions of oral midazolam with ketoconazole, fluoxetine, fluvoxamine, and nefazodone, J. Clin. Pharmacol, 43(11), 1274-1282, 2003. 

The pharmacokinetics of saquinavir is modified by agents that alter isoenzyme CYP3A4 of the cytochrome P-450 system and P-glycoprotein transporter. It should not be administered with midazolam, triazolam and ergot derivatives. The plasma concentrations of saquinavir are lower when coadministered with efavirenz, nevirapine or rifampin. Ritonavir reverses the effects of nevirapine on saquinavir. The coadministration of astemizole, terfenadine, amiodarone, bepridil, quinidine, propafenone or flecainide with saquinavir is also not recommended due to its potential for serious and/or life-threatening reactions. 

Meanwhile, the currently marketed CYP3A4 inducers can profoundly affect the pharmacokinetics of coadministered CYP3A4 substrates, e.g., rifampin on midazolam (139) or triazolam (140). Clearly, the most frequent outcome is a loss of efficacy, which is perhaps less serious than inhibition interactions, although the consequences of coadministering rifampin with the oral contraceptive pill can lead to contraceptive failure (141-143). 

Ahonen J, Olkkola KT, Neuvonen PJ. Effects of itraconazole and terbinafine on the pharmacokinetics and pharmacodynamics of midazolam in healthy volunteers. Br J Clin Pharmacol 1995 40 270-272. 

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