Midazolam systemic clearance

Study Study phase Midazolam systemic clearance (L/hr) Midazolam oral clearance (L/hr) Midazolam bioavailability (%)... 

Dresser et al. administered St. John s wort (LI 160 300 mg t.i.d.) to 20 ethnically diverse individuals and observed a 44% increase in the systemic clearance of midazolam (Table 3) (98). In contrast, the oral clearance of midazolam was increased 1.7-fold (Table 3). The combined changes in midazolam disposition resulted in a significant reduction in the oral bioavailability of midazolam (Table 3). Gurley et al. examined the one-hour 1-hydroxymidazolam-to-midazolam serum ratio and concluded that St. John s wort administration for 28 days resulted in a significant increase in the ratio, which is indicative of CYP3A4 induction (100). 

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... 

Clarithromycin. Oral 4 mg and intravenous 50 micrograni/kg doses of midazolam were given simultaneously to 16 healthy subjects, before and after they took clarithromycin 500 mg twice daily for 7 days. It was found that clarithromycin reduced the systemic clearance of midazolam by about 64%, which resulted in a doubling of the midazolam-induced sleeping time. Similar results were found in another study. ... 

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]. 

BZD hypnotics such as midazolam and triazolam are primarily metabolized via the P450 3A3/4 microenzyme system. Other BZDs often used as hypnotics, such as diazepam, can also be metabolized by CYP 33/4 and CYP 2C19. Any drugs that act as inhibitors or inducers of these isoenzymes could increase or decrease BZD levels, respectively (350). Thus, ketoconazole, macrolide antibiotics (e.g., erythromycin), SSRIs (e.g., fluoxetine-norfluoxetine and fluvoxamine), and other antidepressants (especially nefazodone) may decrease clearance and increase BZD levels to potentially toxic ranges. Conversely, rifampacin, CBZ, and dexamethasone may increase clearance and decrease BZD levels to potentially subtherapeutic ranges. 

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