Hydroxy midazolam

Wrighton, S.A. Ring, B.J. Inhibition of human CYP3A catalyzed I -hydroxy midazolam formation by ketoconazole, nifedipine, erythromycin, cimetidine, and nizatidine. Pharm.Res., 1994, 11, 921-924... 

Modern triple quadrupole instruments can rapidly switch between many SRM transitions within a single acquisition cycle (MRM), enabling the measurement of multiple analytes simultaneously. It is critical to choose a unique molecular ion and product ion pair (the SRM transition ) for specific monitoring of the targeted analyte. An example of liquid chromatography-multiple reaction monitoring (LC-MRM) analysis of midazolam and its two major metabolites, T-hydroxymidazolam and 4-hydroxy midazolam, is shown in Figure 6.2 [18]. 

Figure 4.6 Multiple-injection chromatogram from rapid-fire MS/MS for F-hydroxymidazolam and its internal standard, Cs-hydroxy-midazolam. Adapted from Brown, A., et al. Rapid Commun. Mass Sp. 2010, with permission.

A4 Acetaminophen, alfentanil, amiodarone, astemizole, cocaine, cortisol, cyclosporine, dapsone, diazepam, dihydroergotamine, dihydropyridines, diltiazem, ethinyl estradiol, gestodene, indinavir, lidocaine, lovastatin, macrolides, methadone, miconazole, midazolam, mifepristone (RU 486), paclitaxel, progesterone, quinidine, rapamycin, ritonavir, saquinavir, spironolactone, sulfamethoxazole, sufentanil, tacrolimus, tamoxifen, terfenadine, testosterone, tetrahydro-cannabinol, triazolam, troleandomycin, verapamil Barbiturates, carbamazepine, macrolides, glucocorticoids, pioglitazone, phenytoin, rifampin Erythromycin, 613-hydroxy cortisol... 

In humans, midazolam is rapidly and almost completely metabolized to its primary f-hydroxy metabolite and, to a much lesser extent, to 4-hydroxymidazolam. Both of these pathways are selectively mediated by CYP3A (311,312). In addition, both intestinal and hepatic microsomes exhibit high midazolam hydrox-ylation activity, which in the case of the liver is significantly correlated with the drug s systemic clearance (313). Moreover, scale-up of such in vitro measures (282) was found to provide an excellent prediction of the in vivo extraction ratios of the two organs (313,314). Liver dysfunction markedly impairs midazolam s elimination (315,316), and plasma levels during the anhepatic phase of liver... 

Prochlorperazine Edisylate Prochlorperazine edisylate is not compatible with sodium chloride solutions containing methyl hydroxybenzoate and propyl hydroxy-benzoate as preservatives, but is compatible with solutions containing benzyl alcohol. Prochlorperazine edisylate salts are incompatible with a number of drugs such as aminophylline, amphotericin, ampicillin sodium, some barbiturates, ben-zylpenicillin salts, calcium gluconate, cefmetazole sodium, cephalothin sodium, chloramphenicol sodium succinate, chlorothiazide sodium, chloramphenicol, morphine sulfate containing phenol, magnesium trisilicate mixture, sodium succinate, chlorothiazide sodium, dimenhydrinate, heparin sodium, hydrocortisone sodium succinate, midazolam hydrochloride, and some sulfonamides.166... 

Midazolam (Versed) Preanesthetic and 1-4 conjugates a-hydroxy glucuronide... 

T. N. Johnson, A. Rostami-Hodjegan, J. M. Goddard, M. S. Tanner, and G. T. Sucker, Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children a pharmacokinetic-pharmacodynamic analysis. Br J Anaesth 89(3) 428-437 (2002). 

Lehmann, B. Boulieu, R. Determination of midazolam and its unconjugated 1-hydroxy metabolite in human plasma by high-performance liquid chromatography. J.ChromatogrB, 1995, 674, 138-142... 

One of the issues with P450 3A4 is which reaction provides the most appropriate index of activity, both in vitro and in vivo. Historically nifedipine oxidation and testosterone 6p-hydroxy-lation were among the first activities identified and are still used in vitro K Midazolam 1 -hydrox-ylation has also been used , in part because of its acceptance for in vivo assays. 

Midazolam 1 -hydroxy lation" " Azamulin Mifepristone- / Diltiazam ... 

Ha, H.R. Rentsch, K.M. Kneer, J. Vonderschmitt, D.J. Determination of midazolam and its alpha-hydroxy metabolite in human plasma and urine hy high-performance liquid chromatography. Ther.Drug Monit, 1993, 15, 338-343... 

Complications of drug analysis were successfully resolved by the combination of TLC with MALDI-MS. TLC combined with MALDI-MS was used for analysis of psychotropic drugs (3,4-methylenedioxy methamphetamine, 4-hydroxy-3-methoxy methamphetamine, 3,4-methylenedioxy amphetamine, methamphetamine, p-hydroxy methamphetamine, amphetamine, ketamine, caffeine, chlorpromazine, triazolam, and morphine) in biological samples [42]. This technique was able to analyze 3,4-methylenedioxy methamphetamine (MDMA) and its metabolites in urine samples without sample dilution, and the detection limit of the MDMA spot was 0.05 ng/ spot. Crecelius and coworkers described the use of TLC with MALDI-MS/MS for the structural analysis of small drug molecules [43]. This method was successfully applied to analyze two representatives of nonsteroidal antiinflammatory drugs (tenoxi-cam and piroxicam), and pharmaceutically active compound UK-137,457 and one of its related substances UK-124,912. The feasibility of UTLC-atmospheric pressure (AP)-MALDI-MS was described for the analysis of small molecules (triazole, midazolam, verapamil, and metaprolol) [44]. The authors compared the selectivity and sensitivity between UTLC- and HPTLC-AP-MALDI-MS. It was observed that UTLC plates provided 10-100 times better sensitivity in MALDI analysis than the conventional... 

In another midazolam assay. Martens and Banditt [8] combined the advantages of a high-mass derivative and the choice of an internal standard as closely related to the target molecule as possible. The authors applied two distinct internal standards, i.e., underivatized medazepam to quantify midazolam, and temazepam, which carries a hydroxyl group amenable to derivatization. The second internal standard was used for quantification of the two hydroxy metabolites, optimizing the conditions of quantification. This technique permits the detection of the minor metabolite 4-OH-MDZ in the range of 0.1 to 5 ng/ml, of 1-OH-MDZ from 1 to 50 ng/ml, and of midazolam itself from 2.5 to 125 ng/ml. 

Microbial hydroxylation is a widely used method for the synthesis of mammalian Phase I metabolites. An example is the synthesis of l -hydroxy[ C4]midazolam (21) using a culture of Beauveria sulfurescens ATCC7159. Of particular interest is the stereo- and regioselective hydroxylation of [butyrate-l- C]compactin (32) by Mucor hiemelus MF5021 (pH 5.3 28 °C, 48 h) to [ CJpravastatin (22) ° of >95% radiochemical purity in 32% yield. 

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