An evaluation of the suitability of intravenous midazolam as an in vivo marker for hepatic cytochrome P4503A activity

Abstract

Phenotyping is used to characterize hepatic drugmetabolizing enzyme activity as influenced by pharmacogenetics and environmental exposure. In many instances, phenotyping for hepatic drug-metabolizing enzyme activity involves the intravenous administration of a suitable biomarker (often a drug) and the determination of its total systemic clearance (CL). This procedure assumes that CL is correlated with the intrinsic hepatic clearance of the drug from plasma (CL int ), a measure of intrinsic hepatic enzyme activity. Ideally, the biomarker used for such evaluations should be completely metabolized by the liver, have a low hepatic extraction ratio (E H ) (ie, E H Յ 0.3), be minimally bound to plasma proteins, and be administered intravenously. 1 Intravenous midazolam is suggested to be an in vivo biomarker of hepatic cytochrome P4503A (CYP3A) activity. Notably, the United States Food and Drug Administration advocates its use for this purpose for in vivo drug metabolism and drug interaction studies. 2,3 Both oral and intravenous midazolam are used in these studies; however, this commentary is limited to discussion of intravenous midazolam. The use of intravenous midazolam as a biomarker of hepatic CYP3A activity assumes that midazolam CL is correlated with the CL int of midazolam, which in turn reflects hepatic CYP3A activity. Although we and other investigators use intra-venous midazolam as an in vivo biomarker of hepatic CYP3A activity for phenotyping and drug interaction evaluations, we have some concerns about whether midazolam CL truly reflects the CL int of midazolam in all instances. This commentary discusses these concerns. WELL-STIRRED MODEL OF HEPATIC CLEARANCETo examine the suitability of midazolam as an in vivo biomarker of hepatic CYP3A activity, we applied the well-stirred model of hepatic clearance. 4 It is appreciated that the well-stirred model oversimplifies midazolam clearance in that gastrointestinal CYP3A also contributes to the elimination of midazolam, thus making a splanchnic model for the elimination of midazolam more appropriate. Splanchnic models, however, are complex and of limited predictive value given that the gastrointestinal tract and liver are perfused in both a parallel and a sequential fashion. 5 As a result, splanchnic clearance is not simply the sum of gastrointestinal and hepatic clearance. 5 The well-stirred model assumes that the liver is a single well-stirred compartment and that unbound drug in hepatic venous blood is in equilibrium with unbound drug in the liver. With this model, the hepatic clearance of a drug (CL H ) can be described by equation 1:where Q H is liver blood flow and f u is the unbound fraction of drug in blood. Application of this model allows prediction of CL H relative to changes in Q H , f u , and CL int . This model equation can be simplified for low (E H Յ 0.3) and high (E H Ն 0.7) hepatic extraction ratio drugs to show which factors predominantly influence CL H in these limiting cases. The hepatic extraction ratio can be described by equation 2 4 :

Dexmedetomidine versus Midazolam for Conscious Sedation in Postoperative Patients Undergoing Flexible Bronchoscopy: A Randomized Study

“…6 − 8 The pharmacokinetic properties of midazolam, however, include significant variability in metabolic clearance and numerous drug−drug interactions. 9,10 Dosedependent respiratory depression, prolonged sedation and cognitive disturbances may occur, particularly in elderly patients and in those with hepatic or renal dysfunction. 11,12 Dexmedetomidine is an α 2 -adrenoreceptor agonist with a unique mechanism of action: it induces sedation via receptors within the locus coeruleus, analgesia via receptors in the spinal cord and attenuation of the stress response without significant respiratory depression.…”

Factors Affecting Cytochrome P-450 3A Activity in Cancer Patients

“…Various noninvasive in vivo probes for evaluating CYP3A activity have been described and several have been shown to correlate with drug clearance (3). The most widely tested and accepted CYP3A probes are midazolam and erythromycin, although selection of the ideal CYP3A-phenotyping probe remains controversial (4,5).…”

“…injection over ϳ1 minute. Breath samples were collected in balloons postinjection at 5,10,15,20,25,30, and 40 minutes. Samples were shipped to Metabolic Solutions for measurement of breath carbon dioxide.…”

Lessons from the CYP3A4 Promoter

“…This is unfortunate, because CYP3A4 is the most abundant hepatic and intestinal cytochrome P450, catalyzes the metabolism of more than half of all drugs, and represents the primary route of elimination for many drugs. Some studies have reported a 10-fold variation in clearance of CYP3A probe drugs (Floyd et al, 2003;Rogers et al, 2003), although 90-fold variability in CYP3A4 protein expression has been reported in liver (Lamba et al, 2002a). Some of the variation occurs because in the general population, CYP3A activity can be influenced by concurrent administration of CYP3A inhibitors and inducers.…”