Using drug probes to monitor hepatic drug metabolism in critically ill patients: midazolam, a flawed but useful tool for clinical investigation of CYP3A activity?

Kirwan, Chris; MacPhee, Iain; Philips, Barbara J.

doi:10.1517/17425255.2010.482929

Cited by 11 publications

(7 citation statements)

References 84 publications

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“…and oral ALF, and had free access to food and water thereafter. Venous blood samples were obtained 0, 2, 5, 10,20,30,45,60,90,120,180,185,190,195,210,225,240,270, 300, 360, 420, 480, 540, 600, and 660 min after i.v. d 0 -ALF (corresponding to 5, 10, 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, and 480 min after oral d 3 -ALF) on sequential dosing session days and at 0, 2, 5, 10, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, 360, 420, and 480 min after i.v.…”

Section: Discussionmentioning

confidence: 99%

“…1 Considerable effort has been expended toward identifying and developing an in vivo probe for assessment of human hepatic and intestinal CYP3A activity (or phenotype), prediction of CYP3A-dependent drug metabolism, and individualized dosing of CYP3A drugs with narrow therapeutic indexes. [6][7][8][9][10] US Food and Drug Administration regulations for new drug development require clinical assessment of potential drug interactions and, preferably, their consequences. Clinically, there is profound interest in using CYP3A activity assessment to predict optimal dosing, improve therapeutic efficacy, and minimize adverse drug effects.…”

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confidence: 99%

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Concurrent Assessment of Hepatic and Intestinal Cytochrome P450 3A Activities Using Deuterated Alfentanil

Kharasch

Vangveravong

Buck

et al. 2011

Clin Pharmacol Ther

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Alfentanil is a validated probe for hepatic, first-pass, and intestinal cytochrome P450 (CYP) 3A activity, using plasma clearances, single-point concentrations and noninvasive pupil diameter change (miosis). Assessing intravenous and oral drug disposition typically requires separate dosing. This investigation evaluated concurrent administration of oral deuterated and intravenous unlabeled alfentanil, to assess both intestinal and hepatic CYP3A, and compare sequential and simultaneous dosing. Alfentanil disposition was evaluated after strong hepatic and/or intestinal CYP3A induction and inhibition by rifampin, ketoconazole, and grapefruit juice. Using plasma alfentanil concentrations and area under the curve, clearance, or single-point concentrations, both simultaneous and sequential dosing provided equivalent results and detected hepatic and intestinal CYP3A induction and inhibition. Miosis better detected CYP3A modulation with sequential vs simultaneous dosing. These results show that concurrent oral deuterated and intravenous alfentanil, administered either sequentially or simultaneously, is an efficient and effective approach to assessing hepatic and intestinal CYP3A activity.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Concurrent Assessment of Hepatic and Intestinal Cytochrome P450 3A Activities Using Deuterated Alfentanil

Kharasch

Vangveravong

Buck

et al. 2011

Clin Pharmacol Ther

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“…People homozygous for CYP3A5*3 produce a non-functioning CYP3A5 protein which is the predominant form in 80% of Caucasian populations. The wild type predominates in Sub-Saharan Africans [38], 60% are homozygous for CYP3A5*1 . Other CYP enzymes involved in drug metabolism in humans include CYP1A, CYP2C19, CYP2C9 and CYP2D6, together they account for 80% of all drug metabolism [39].…”

Section: Potential Mechanisms Of How Aki Affects Non-renal Drug Clearmentioning

confidence: 99%

Xenobiotic Metabolism: The Effect of Acute Kidney Injury on Non-Renal Drug Clearance and Hepatic Drug Metabolism

Dixon

Lane

MacPhee

et al. 2014

IJMS

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Acute kidney injury (AKI) is a common complication of critical illness, and evidence is emerging that suggests AKI disrupts the function of other organs. It is a recognized phenomenon that patients with chronic kidney disease (CKD) have reduced hepatic metabolism of drugs, via the cytochrome P450 (CYP) enzyme group, and drug dosing guidelines in AKI are often extrapolated from data obtained from patients with CKD. This approach, however, is flawed because several confounding factors exist in AKI. The data from animal studies investigating the effects of AKI on CYP activity are conflicting, although the results of the majority do suggest that AKI impairs hepatic CYP activity. More recently, human study data have also demonstrated decreased CYP activity associated with AKI, in particular the CYP3A subtypes. Furthermore, preliminary data suggest that patients expressing the functional allele variant CYP3A5*1 may be protected from the deleterious effects of AKI when compared with patients homozygous for the variant CYP3A5*3, which codes for a non-functional protein. In conclusion, there is a need to individualize drug prescribing, particularly for the more sick and vulnerable patients, but this needs to be explored in greater depth.

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“…It should be mentioned, however, that one study reported a decreased clearance of the CYP3A substrate midazolam 1-12 months after transplantation compared with 7 days after transplantation (de Jonge et al, 2015). Although midazolam is considered a gold standard CYP3A probe drug, it is also highly bound to plasma proteins (Kirwan et al, 2010). Albumin levels are reported to be reduced in patients with chronic kidney disease and after recent surgery (Meijers et al, 2008;Hubner et al, 2016) and increase with time after transplantation (Størset et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Recovery of CYP3A Phenotype after Kidney Transplantation

et al. 2017

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End-stage renal disease impairs drug metabolism via cytochrome P450 CYP3A; however, it is unclear whether CYP3A activity recovers after kidney transplantation. Therefore, the aim of this study was to evaluate the change in CYP3A activity measured as 4-hydroxycholesterol (4OHC) concentration after kidney transplantation. In total, data from 58 renal transplant recipients with 550 prospective 4OHC measurements were included in the study. One sample per patient was collected before transplantation, and 2-12 samples per patient were collected 1-82 days after transplantation. The measured pretransplant 4OHC concentrations ranged by >7-fold, with a median value of 22.8 ng/ml. Linear mixed-model analysis identified a 0.16-ng/ml increase in 4OHC concentration per day after transplantation ( < 0.001), indicating a regain in CYP3A activity. Increasing estimated glomerular filtration rate after transplantation was associated with increasing 4OHC concentration ( < 0.001), supporting that CYP3A activity increases with recovering uremia. In conclusion, this study indicates that CYP3A activity is regained subsequent to kidney transplantation.

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Using drug probes to monitor hepatic drug metabolism in critically ill patients: midazolam, a flawed but useful tool for clinical investigation of CYP3A activity?

Abstract: Critically ill patients are difficult to manage but methods are now available for investigation of complex interrelationships that complicate the care and management of these patients with the potential to improve safety, efficacy and outcome, particularly for drug administration.

Cited by 11 publications

References 84 publications

Concurrent Assessment of Hepatic and Intestinal Cytochrome P450 3A Activities Using Deuterated Alfentanil

Concurrent Assessment of Hepatic and Intestinal Cytochrome P450 3A Activities Using Deuterated Alfentanil

Xenobiotic Metabolism: The Effect of Acute Kidney Injury on Non-Renal Drug Clearance and Hepatic Drug Metabolism

Recovery of CYP3A Phenotype after Kidney Transplantation

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