Midazolam clearance

Wong M, Balleine RL, Collins M, Liddle C, Clarke CL, Gurney H. CYP3A5 genotype and midazolam clearance in Australian patients receiving chemotherapy. Clin Pharmacol Ther 2004 75 529-538. 

Thummel KE, Shen DD, Carithers RL, et al. Prediction of in vivo midazolam clearance from hepatic CYP3A content and midazolam 1-hydroxylation activity in bver transplant patients. ISSX Proc 1993 4 235. 

Other CYP3A4 inducers have also been reported to exert a pronounced effect on oral midazolam AUC (78), presumably through induction of intestinal and hepatic CYP3A4. For example, administration of phenytoin and carba-mazepine led to a 94% reduction in midazolam AUC compared with an untreated control population. Induction of CYP3A by St. John s wort, a widely used herbal supplement for the treatment of mild to moderate depression, has also attracted considerable interest. The major bioactive ingredient of St. John s wort, hyperforin, is a very potent in vitro activator of hPXR (79,80). Several groups have investigated induction of midazolam clearance by St. John s wort (81-83). As in the case of rifampin, clearance of oral midazolam... 

Midazolam clearance has been found to correlate with hepatic CYP3A levels (Thummel 1994) as well as ERMBT results (Lown 1992). However weak, inconstant or lack of correlations between midazolam and ERBT test results have been observed, which could be explained by binding to different CYP3A active sites. In addition, contrary to the midazolam test, the ERMBT does not measure CYP3 A5 activity. 

A single 4-hour single blood sampling for midazolam assay has been retrospectively found an excellent estimator for iv or oral midazolam clearance determination (Lin 2001). 

Pharmacokinetic and pharmacodynamic interactions of midazolam with fluoxetine, fluvoxamine, nefazodone, and ketoconazole have been investigated in 40 healthy subjects (64). The mean AUC of midazolam was increased 772% by ketoconazole and 444% by nefazodone. However, fluoxetine and fluvoxamine had no significant effects. Nefazodone and ketoconazole caused significant increases in midazolam-related cognitive impairment, reflecting changed midazolam clearance. 

Drugs that inhibit CYP450 3A4, such as nefazodone and fluvoxamine, may reduce midazolam clearance and thus raise midazolam levels... 

Half-life may be longer In obese patients Patients with premenstrual syndrome may be less sensitive to midazolam than healthy women throughout the cycle Midazolam clearance may be reduced In postmenopausal women compared to premenopausal women... 

The majority of allelic variants identified for CYP3 A4 and 3 A5 either have no phenotypic effect or result in diminished catalytic activity, which can result in an increase in circulating drug levels to some extent. A rare allelic form of CYP3A4 recently discovered in a German subject with a midazolam clearance of 2.99 mL (min kg)-1 has been shown to be due to the lack of heme incorporation into the heterologously expressed protein [192], The frequency of this variant in the general population has... 

Oral midazolam clearance Rif induction intestinal CYP3A ... 

Thummel, K.E., D.D. Shen, R.L. Carithers, Jr., P. Hartwell, T.D. Podoll, W.F. Trager et al. (1993). Prediction of in vivo midazolam clearance from hepatic CYP3A content and midazolam 1 -hydrox-ylation activity in liver transplant patients. In Abstracts, 5th North American ISSX Meeting, Vol. 4. p. 235, 17-21 October, Tucson, AZ. 

He P, Court M H, Greenblatt D J, et al. (2005). Genotype-phenotype associations of cytochrome P450 3A4 and 3A5 polymorphism with midazolam clearance in vivo. Clin. Pharmacol. Ther. 71 313-318. 

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