Impact of the CYP3A5 genotype on midazolam pharmacokinetics and pharmacodynamics during intensive care sedation

Fromm, Martin F.; Schwilden, H.; Bachmakov, Iouri; König, Jörg; Bremer, Frank; Schüttler, J.

doi:10.1007/s00228-007-0365-6

Cited by 14 publications

(14 citation statements)

References 24 publications

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“…In addition to measuring the CYP3A-activity, the 4b-hydroxycholesterol ratio and 6b-hydroxycortisol ratio are also affected by the CYP3A5 genotype Hassan et al, 2013). In contrast, midazolam clearance is not affected by the CYP3A5 genotype in vivo (Fromm et al, 2007;Kharasch et al, 2007;Tomalik-Scharte et al, 2008;Miao et al, 2009). In Caucasians, few individuals express CYP3A5, as demonstrated here with only two subjects of 24 having one active CYP3A5 allele, similar to earlier reports .…”

Section: Discussionsupporting

confidence: 90%

Comparison of Endogenous 4β-Hydroxycholesterol with Midazolam as Markers for CYP3A4 Induction by Rifampicin

et al. 2013

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CYP3A4, considered the most important enzyme in drug metabolism, is often involved in drug-drug interactions. When developing new drugs, appropriate markers for detecting CYP3A4 induction are needed. Our study compared endogenously formed 4β-hydroxycholesterol with the midazolam clearance in plasma and the 6β-hydroxycortisol/cortisol ratio in urine as markers for CYP3A4 induction. To this end, we performed a clinical trial in which 24 healthy subjects were randomized to 10, 20, or 100 mg daily doses of rifampicin for 14 days (n = 8 in each group) to achieve a low and moderate CYP3A4 induction. The CYP3A4 induction could be detected even at the lowest dose of rifampicin (10 mg) via the estimated midazolam clearance, the 4β-hydroxycholesterol ratio (both P < 0.01), and the 6β-hydroxycortisol ratio (P < 0.05). For the three dosing groups (10, 20, and 100 mg), the median fold induction from baseline was 2.0, 2.6, and 4.0 for the estimated midazolam clearance; 1.3, 1.6, and 2.5 for the 4β-hydroxycholesterol/cholesterol ratio; and 1.7, 2.9, and 3.1 for the 6β-hydroxycortisol/cortisol ratio. In conclusion, the 4β-hydroxycholesterol ratio is comparable to midazolam clearance as a marker of CYP3A4 induction, and each may be used to evaluate CYP3A4 induction in clinical trials evaluating drug-drug interactions for new drugs.

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Section: Discussionsupporting

confidence: 90%

Comparison of Endogenous 4β-Hydroxycholesterol with Midazolam as Markers for CYP3A4 Induction by Rifampicin

et al. 2013

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“…Midazolam is mainly a marker of CYP3A4 [27][32], while the 4b-OHC/cholesterol ratio and 4b-OHC are markers of the 9 (16) combined activity of CYP3A4 and CYP3A5 [7,28] [3,33]. In the present study, only three mothers and three children had one functional CYP3A5*1 allele, thus expressing CYP3A5.…”

Section: Discussionmentioning

confidence: 76%

“…Pregnancy increases the activity of a number of hepatic enzymes, e. g. CYP3A4 [16][17][18][ [21][22][23], CYP2D6 [18][19][20][ [23][24][25] and CYP2C9 [16] [21], while it decreases the activity of some others, such as CYP1A2 [18,21] [23,26] and CYP2C19 [22] [27]. The altered enzyme activities during pregnancy may be due to increased levels of progesterone and estrogen and/or fetal enzyme activity [16] [21].…”

Section: Introductionmentioning

confidence: 99%

Cytochrome P450 3A activity in mothers and their neonates as determined by plasma 4β-hydroxycholesterol

Nylén

Sergel

Forsberg

et al. 2011

Eur J Clin Pharmacol

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PurposeThe purpose of this study was to determine the 4 -hydroxycholesterol to cholesterol ratio in mothers and neonates at the time of birth and four months post partum.Method 21 mothers and 22 neonates were recruited at the delivery ward at Karolinska University Hospital, Huddinge,Sweden. Blood samples taken from mothers and neonates at birth and four months post partum were analyzed for 4 -hydroxycholesterol and cholesterol. ResultsThe median plasma concentration of 4 -hydroxycholesterol was higher in mothers at delivery (50 ng/mL) compared to healthy non-pregnant women (29 ng/mL). The pregnant women had a higher median cholesterol concentration (6.2 mmol/L) compared to healthy non-pregnant women (4.6 mmol/L) but this could only partly explain the increased 4 -hydroxycholesterol. The major cause is an increased CYP3A activity during pregnancy. The median 4 -hydroxycholesterol/cholesterol ratio•10 4 was elevated in mothers at time of birth compared to non-pregnant women (0.19 and 0.15, respectively) but decreased to 0.15 four months post partum.Neonates had a median 4 -hydroxycholesterol/cholesterol ratio•10 4 (0.19) comparable to adults already at birth, but lower 4 -hydroxycholesterol (12 ng/mL) and cholesterol (1.8 mmol/L) concentrations. ConclusionPregnancy leads to increased CYP3A enzyme activity as determined by the 4 -hydroxycholesterol/cholesterol ratio. Neonates have low 4 -hydroxycholesterol and cholesterol concentrations but similar total CYP3A activity as adults already at birth.

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“…The clinical impact of the CYP3A5 polymorphism is ambiguous, with some CYP3A substrates reportedly affected by the CYP3A5 genotype such as tacrolimus (Barry and Levine, 2010), verapamil (Jin et al, 2007), and cyclosporine (Zhu et al, 2010) and others not affected such as midazolam (Fromm et al, 2007), alfentanil (Kharasch et al, 2007), and nifedipine (Fukuda et al, 2004). The CYP3A5 polymorphism is also a likely contributor to the large interindividual variability in pharmacokinetics observed for some CYP3A substrates.…”

Section: Introductionmentioning

confidence: 99%

Selective Mechanism-Based Inactivation of CYP3A4 by CYP3cide (PF-04981517) and Its Utility as an In Vitro Tool for Delineating the Relative Roles of CYP3A4 versus CYP3A5 in the Metabolism of Drugs

et al. 2012

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CYP3cide (PF-4981517; 1-methyl-3-[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]-4-[(3S)-3-piperidin-1-ylpyrrolidin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine) is a potent, efficient, and specific time-dependent inactivator of human CYP3A4. When investigating its inhibitory properties, an extreme metabolic inactivation efficiency (k inact /K I ) of 3300 to 3800 ml ⅐ min ؊1 ⅐ mol ؊1 was observed using human liver microsomes from donors of nonfunctioning CYP3A5 (CYP3A5 *3/*3). This observed efficiency equated to an apparent K I between 420 and 480 nM with a maximal inactivation rate (k inact ) equal to 1.6 min ؊1 . Similar results were achieved with testosterone, another CYP3A substrate, and other sources of the CYP3A4 enzyme. To further illustrate the abilities of CYP3cide, its partition ratio of inactivation was determined with recombinant CYP3A4. These studies produced a partition ratio approaching unity, thus underscoring the inactivation capacity of CYP3cide. WhenCYP3cide was tested at a concentration and preincubation time to completely inhibit CYP3A4 in a library of genotyped polymorphic CYP3A5 microsomes, the correlation of the remaining midazolam 1-hydroxylase activity to CYP3A5 abundance was significant (R 2 value equal to 0.51, p value of <0.0001). The work presented here supports these findings by fully characterizing the inhibitory properties and exploring CYP3cide's mechanism of action. To aid the researcher, multiple commercially available sources of CYP3cide were established, and a protocol was developed to quantitatively determine CYP3A4 contribution to the metabolism of an investigational compound. Through the establishment of this protocol and the evidence provided here, we believe that CYP3cide is a very useful tool for understanding the relative roles of CYP3A4 versus CYP3A5 and the impact of CYP3A5 genetic polymorphism on a compound's pharmacokinetics.

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Impact of the CYP3A5 genotype on midazolam pharmacokinetics and pharmacodynamics during intensive care sedation

Cited by 14 publications

References 24 publications

Comparison of Endogenous 4β-Hydroxycholesterol with Midazolam as Markers for CYP3A4 Induction by Rifampicin

Comparison of Endogenous 4β-Hydroxycholesterol with Midazolam as Markers for CYP3A4 Induction by Rifampicin

Cytochrome P450 3A activity in mothers and their neonates as determined by plasma 4β-hydroxycholesterol

Selective Mechanism-Based Inactivation of CYP3A4 by CYP3cide (PF-04981517) and Its Utility as an In Vitro Tool for Delineating the Relative Roles of CYP3A4 versus CYP3A5 in the Metabolism of Drugs

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