In vivo comparisons of constitutive cytochrome P450 3A activity assessed by alprazolam, triazolam, and midazolam

Masica, Andrew L.; Mayo, Gail; Wilkinson, Grant R.

doi:10.1016/j.clpt.2004.07.003

Cited by 60 publications

(49 citation statements)

References 48 publications

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“…K i,iv for the *1/*1, *1/*X, and *X/*X groups was 30 Ϯ 12, 77 Ϯ 72, and 58 Ϯ 53 M, respectively. As has been reported previously (Kinirons et al, 1999;Masica et al, 2004), a correlation was not evident between midazolam Cl (whether normalized to body weight) and the ERMBT in both the presence and absence of fluconazole (r s Յ 0.27, p Ն 0.28).…”

Section: Resultssupporting

confidence: 56%

The Influence of CYP3A5 Expression on the Extent of Hepatic CYP3A Inhibition Is Substrate-Dependent: An in Vitro-in Vivo Evaluation

Isoherranen

Ludington²,

Givens³

et al. 2007

Drug Metab Dispos

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ABSTRACT:Despite several studies suggesting that CYP3A5 expression can influence the extent of hepatic CYP3A-mediated inhibition, a systematic in vitro-in vivo evaluation of this potential clinically important issue has not been reported. Using representative probes from two distinct CYP3A substrate subgroups (midazolam, erythromycin), the inhibitory potency of fluconazole was evaluated in pooled human liver microsomes (HLM) with a low or high specific CYP3A5 content, in recombinant CYP3A enzymes (rCYP3A), and in healthy volunteers lacking or carrying the CYP3A5*1 allele. Fluconazole was a slightly more potent inhibitor of CYP3A activity in CYP3A5؊ HLM than in CYP3A5؉ HLM with midazolam (K i of 15 and 25 M, respectively) but not with erythromycin (IC 50 of 70 and 54 M, respectively). In comparison, fluconazole was a much more potent inhibitor of rCYP3A4 than rCYP3A5 with both midazolam (K i of 7.7 and 54 M, respectively) and erythromycin (IC 50 of 100 and 350 M, respectively). As predicted from HLM, with i.v. midazolam, the average (؎ S.D.) in vivo K i (K i,iv ) was significantly higher in CYP3A5*1 carriers (24 ؎ 17 and 17 ؎ 8 M for homozygous and heterozygous groups, respectively) than in noncarriers (13 ؎ 6 M) (p ‫؍‬ 0.02). With the erythromycin breath test, the average K i,iv was not different between homozygous CYP3A5*1 carriers (30 ؎ 12 M) and noncarriers (58 ؎ 53 M). In conclusion, the effect of CYP3A5 on hepatic CYP3A-mediated inhibitory drug-drug interactions is substrate-dependent, and HLM, rather than rCYP3A, are the preferred in vitro system for predicting these interactions in vivo.Adverse interactions between two or more medications have been a longstanding problem in clinical practice. Such interactions frequently result from one drug impairing the elimination of another, which can lead to increased systemic concentrations of the affected drug and the potential for an adverse or toxic reaction. The cytochrome P450 3A (CYP3A) subfamily, consisting primarily of CYP3A4 and CYP3A5 in adults, is believed to participate in the metabolism of more than half of therapeutic agents that undergo oxidation (Wilkinson, 2005). Taken together, inhibition of CYP3A-mediated metabolism is a common mechanism underlying numerous drug-drug interactions. In addition, the extent of inhibition of CYP3A-mediated drug clearance by a comedicant often varies between individuals, making it difficult to predict the magnitude and severity of the interaction.Both CYP3A4 and CYP3A5 are expressed primarily in the liver and small intestine. Although more than 30 allelic variants in the CYP3A4 gene have been identified, low-variant frequencies, often combined with a lack of functional consequence, indicate a limited contribution by these variants to the large interindividual variation observed in CYP3A4 expression Wojnowski, 2004). In contrast, CYP3A5 expression is clearly polymorphic, and the frequency of robust expression of a functionally significant protein results from genetic mutations that vary among different ethnic groups Xie...

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Section: Resultssupporting

confidence: 56%

The Influence of CYP3A5 Expression on the Extent of Hepatic CYP3A Inhibition Is Substrate-Dependent: An in Vitro-in Vivo Evaluation

Isoherranen

Ludington²,

Givens³

et al. 2007

Drug Metab Dispos

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“…administration data) (Hall et al, 1999) indicates that the extent to which the CYP3A4 substrates are extracted by the intestine and liver varies considerably from drug to drug, in agreement with the lack of coordination in regulation of CYP3A4 expression in liver and intestine . In the case of alprazolam and quinidine, intestinal extraction is significantly lower compared with hepatic (Damkier et al, 1999;Hirota et al, 2001), whereas for certain substrates (e.g., triazolam, atorvastatin, and tacrolimus) intestinal extraction rivals or even exceeds that of the liver (Floren et al, 1997, Lennernas, 2003Masica et al, 2004). The clinical relevance of the intestinal metabolism depends on the relative importance of the metabolic pathway involved and possible interplay with P-glycoprotein.…”

mentioning

confidence: 99%

Intestinal and Hepatic Metabolic Activity of Five Cytochrome P450 Enzymes: Impact on Prediction of First-Pass Metabolism

Galetin¹,

Houston²

2006

J Pharmacol Exp Ther

132

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The contribution of the gut is not routinely incorporated into in vitro-in vivo predictions of either clearance or drug-drug interactions, and this omission may partially explain the general underprediction trend often observed. In the current study, the metabolic ability of hepatic and intestinal pooled microsomes was compared for eight CYP3A substrates (midazolam, triazolam, diazepam, alprazolam, flunitrazepam, nifedipine, testosterone, and quinidine) and paclitaxel, tolbutamide, S-mephenytoin, and bufuralol as CYP2C8, CYP2C9, CYP2C19, and CYP2D6 probes, respectively. A general agreement in the type of kinetics was observed between the two systems for the substrates investigated. Of the 16 pathways investigated, 75% of K m (S 50 ) values obtained in intestinal microsomes (5.9 -769 M) were within 2-fold of hepatic estimates. Irrespective of the cytochrome P450 (P450) investigated and normalization of V max values for the P450 abundance, clearance was 4.5-to 50-fold lower in intestinal microsomes (0.0005-0.51 l/min/ P450) compared with the hepatic estimates (0.002-5.8 l/min/ P450), whereas the rank order was consistent between the systems. Assessment of two enterocyte isolation methods (mucosal scraping or enterocyte elution) was performed at the substrate concentrations corresponding to the determined V max conditions for 11 pathways. The activity difference between the methods (3-29-fold) was P450-related in the following rank order: CYP2C19 Ͼ CYP3A4 Ͼ CYP2C9 ϳ CYP2D6. After correction for the loss of activity between the methods, the intrinsic activities of hepatic and intestinal CYP3A4, CYP2C9, CYP2C19, and CYP2D6 were comparable for the 16 pathways. The implications of these findings on the prediction of intestinal first-pass metabolism are discussed.

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“…The interindividual and study-to-study variability in mean exposure observed for the current study and the absolute bioavailability study may be a consequence of the variability in the intestinal gut expression of CYP3A4 in individuals. A 6-fold range in exposures is in keeping with observations for other drugs that are CYP3A4 substrates and that are metabolized by the gut (Masica et al, 2004).…”

Section: Discussionmentioning

confidence: 78%

“…Across structurally diverse and highly related species, the relationship between extraction due to metabolism at the gut and liver has not been clear. With benzodiazepines, F g estimates for alprazolam, triazolam, and midazolam are 0.05, 0.6, and 0.5, respectively despite only a single atom difference for triazolam and alprazolam (Masica et al, 2004). The challenges in predicting intestinal metabolism are further exemplified by several drugs that are predominantly cleared by CYP3A4 (e.g., simvastatin, buspirone, lovastatin, and tacrolimus), which have low-to-moderate hepatic CL (as determined by liver microsomes), but are extracted by the gut very extensively (Yang et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

Absorption, Metabolism, Excretion, and the Contribution of Intestinal Metabolism to the Oral Disposition of [14C]Cobimetinib, a MEK Inhibitor, in Humans

Takahashi

Choo

et al. 2015

Drug Metabolism and Disposition

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The pharmacokinetics, metabolism, and excretion of cobimetinib, a MEK inhibitor, were characterized in healthy male subjects (n = 6) following a single 20 mg (200 mCi) oral dose. Unchanged cobimetinib and M16 (glycine conjugate of hydrolyzed cobimetinib) were the major circulating species, accounting for 20.5% and 18.3% of the drug-related material in plasma up to 48 hours postdose, respectively. Other circulating metabolites were minor, accounting for less than 10% of drug-related material in plasma. The total recovery of the administered radioactivity was 94.3% (61.6%, S.D.) with 76.5% (62.3%) in feces and 17.8% (62.5%) in urine. Metabolite profiling indicated that cobimetinib had been extensively metabolized with only 1.6% and 6.6% of the dose remaining as unchanged drug in urine and feces, respectively. In vitro phenotyping experiments indicated that CYP3A4 was predominantly responsible for metabolizing cobimetinib. From this study, we concluded that cobimetinib had been well absorbed (fraction absorbed, F a = 0.88). Given this good absorption and the previously determined low hepatic clearance, the systemic exposures were lower than expected (bioavailability, F = 0.28). We hypothesized that intestinal metabolism had strongly attenuated the oral bioavailability of cobimetinib.

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In vivo comparisons of constitutive cytochrome P450 3A activity assessed by alprazolam, triazolam, and midazolam

Cited by 60 publications

References 48 publications

The Influence of CYP3A5 Expression on the Extent of Hepatic CYP3A Inhibition Is Substrate-Dependent: An in Vitro-in Vivo Evaluation

The Influence of CYP3A5 Expression on the Extent of Hepatic CYP3A Inhibition Is Substrate-Dependent: An in Vitro-in Vivo Evaluation

Intestinal and Hepatic Metabolic Activity of Five Cytochrome P450 Enzymes: Impact on Prediction of First-Pass Metabolism

Absorption, Metabolism, Excretion, and the Contribution of Intestinal Metabolism to the Oral Disposition of [14C]Cobimetinib, a MEK Inhibitor, in Humans

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