Appropriate Phenotyping Procedures for Drug Metabolizing Enzymes and Transporters in Humans and Their Simultaneous Use in the “Cocktail” Approach

Fuhr, Uwe; Jetter, Alexander; Kirchheiner, Julia

doi:10.1038/sj.clpt.6100050

Cited by 216 publications

(197 citation statements)

References 96 publications

Supporting

Mentioning

190

Contrasting

Unclassified

Order By: Relevance

“…When used as a CYP3A probe in drug interaction studies, midazolam doses are lower than the doses used during anaesthetic induction or sedation of patients and usually range between 1-4 mg [10]. We have previously shown that oral doses of midazolam exhibit linear pharmacokinetics over a 30 000-fold range and that oral microdoses can successfully predict drug interactions with strong inhibitors of CYP3A in healthy volunteers [11] and patients with haematological diseases [12].…”

Section: Introductionmentioning

confidence: 99%

Midazolam microdose to determine systemic and pre‐systemic metabolic CYP3A activity in humans

Hohmann

Kocheise

Carls

et al. 2015

Brit J Clinical Pharma

View full text Add to dashboard Cite

AIMWe aimed to establish a method to assess systemic and pre-systemic cytochrome P450 (CYP) 3A activity using ineffective microgram doses of midazolam. METHODSIn an open, one sequence, crossover study, 16 healthy participants received intravenous and oral midazolam at microgram (0.001 mg intravenous and 0.003 mg oral) and regular milligram (1 mg intravenous and 3 mg oral) doses to assess the linearity of plasma and urine pharmacokinetics. RESULTS Dose CONCLUSIONThe pharmacokinetics of an intravenous midazolam microdose is linear to the applied regular doses and can be used to assess safely systemic CYP3A activity and, in combination with oral microdoses, pre-systemic CYP3A activity. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Midazolam pharmacokinetics of oral doses are linear over a 30 000-fold range.• An oral microdose of midazolam is suitable to measure total CYP3A activity.• CYP3A inhibition with strong inhibitors can be evaluated with a microdose in healthy volunteers and patients. WHAT THIS STUDY ADDS• The pharmacokinetics of intravenous midazolam microdoses are linear to milligram doses.• The bioavailability and metabolic clearance of midazolam is similar after administration of microdoses and milligram doses.• Midazolam microdoses are a suitable tool to assess both systemic and pre-systemic CYP3A activity.

show abstract

Section: Introductionmentioning

confidence: 99%

Midazolam microdose to determine systemic and pre‐systemic metabolic CYP3A activity in humans

Hohmann

Kocheise

Carls

et al. 2015

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…From 4 hours after dosing on, this ratio remains unchanged for at least another 12 hours and thus is robust against deviations in urine sampling [14]. Therefore, the results of NAT2 phenotyping are considered as reliable from both a scientific and technical point of view and, as for any valid phenotyping procedure, may provide information beyond genotyping [15]. It should be mentioned that the metabolic caffeine ratio has been shown to reflect the activity of hepatic NAT2 [16], but activity differences between NAT2 genotypes most probably also apply to intestinal tissue [17].…”

Section: Discussionmentioning

confidence: 99%

Mesalazine pharmacokinetics and NAT2 phenotype

Lück

Kinzig

Jetter

et al. 2008

Eur J Clin Pharmacol

View full text Add to dashboard Cite

BACKGROUND: Mesalazine undergoes extensive metabolism by N-acetylation. While there is some evidence for an involvement of N-acetyltransferase (NAT) type 1, a potential role of NAT type 2 (NAT2) in vivo has not been tested. METHODS: In two studies in healthy young Caucasians, NAT2 phenotyping was carried out using a caffeine metabolic ratio in urine 4-6 h postdose. In study A, 1,000 mg mesalazine doses were given thrice daily for 5 days, and urine and blood samples were drawn during the last dosing interval. In study B, a 1,000 mg single dose was given, and samples were taken for 48 h postdose. Pharmacokinetics of mesalazine and N-acetylmesalazine (LC-MS/MS) were calculated by noncompartmental methods. RESULTS: NAT2 phenotype could be allocated unequivocally in 21 slow and 5 rapid acetylators in study A, and in 9 slow and 8 rapid acetylators in study B. Geometric mean (CV%) values in study A for slow [rapid] acetylators were as follows: mesalazine AUC 11.1 microg/mL.h (51%) [12.0 microg/mL.h (52%)], N-acetylmesalazine AUC 27.7 microg/mL.h (32%) [30.5 microg/mL.h (27%)], mesalazine Ae 8.53% (89%) Statistics provided no evidence for a true difference in mesalazine pharmacokinetics between slow and rapid acetylators, and no significant correlation between NAT2 activity and any mesalazine pharmacokinetic parameter was found. CONCLUSION: NAT2 has no major role in human metabolism of mesalazine in vivo.

show abstract

“…Multiple probe drugs and phenotyping protocols have been described for different CYP450 enzymes, amongst which several have been validated to provide a reliable estimate of the actual enzyme activity. We refer to the work of Streetman et al [11] and Fuhr et al [12] for an overview of available phenotyping procedures. Fuhr et al also discussed the requirements for appropriate phenotyping procedures.…”

Section: Introductionmentioning

confidence: 99%

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

2015

View full text Add to dashboard Cite

Interindividual variability in the expression and function of drug metabolizing cytochrome P (CYP) 450 enzymes, determined by a combination of genetic, non-genetic and environmental parameters, is a major source of variable drug response. Phenotyping by administration of a selective enzyme substrate, followed by the determination of a specific phenotyping metric, is an appropriate approach to assess the in vivo activity of CYP450 enzymes, as it takes into account all influencing factors. A phenotyping protocol should be as simple and convenient as possible. Typically, phenotyping metrics are determined in traditional matrices, such as blood, plasma or urine. Several sampling strategies have been proposed as an alternative for these traditional sampling techniques.In this review, we provide a comprehensive overview of available methods using dried blood spots, hair, oral fluid, exhaled breath and sweat for in vivo CYP450 phenotyping. We discuss the relation between phenotyping metrics measured in these samples and those in conventional matrices, along with the advantages and limitations of the alternative sampling techniques. Reliable phenotyping procedures for several clinically relevant CYP450 enzymes, including CYP1A2, CYP2C19 and CYP2D6, are currently available for oral fluid, breath or dried blood spots, while additional studies are needed for other CYP450 isoforms, such as CYP3A4. The role of hair analysis for this purpose remains to be established. Being non-or minimally invasive, these sampling strategies provide convenient and patient-friendly alternatives for classical phenotyping procedures, which may contribute to the implementation of CYP450 phenotyping in clinical practice. 4 Key Points Phenotyping by administration of a selective probe drug, followed by determination of a specific phenotyping metric, allows to assess the in vivo enzyme activity of CYP450 enzymes, taking into account genetic, non-genetic and environmental influencing factors. In addition to classical sampling techniques, such as blood or urine collection, reliable phenotyping procedures for several clinically relevant CYP450 enzymes are currently available for oral fluid, breath and dried blood spots.

show abstract

Appropriate Phenotyping Procedures for Drug Metabolizing Enzymes and Transporters in Humans and Their Simultaneous Use in the “Cocktail” Approach

Cited by 216 publications

References 96 publications

Midazolam microdose to determine systemic and pre‐systemic metabolic CYP3A activity in humans

Midazolam microdose to determine systemic and pre‐systemic metabolic CYP3A activity in humans

Mesalazine pharmacokinetics and NAT2 phenotype

Alternative Sampling Strategies for Cytochrome P450 Phenotyping

Contact Info

Product

Resources

About