In vitro forecasting of drugs which may interfere with the biotransformation of midazolam

Gascon, Marie-Paule; Dayer, P.

doi:10.1007/bf00314987

Cited by 91 publications

(53 citation statements)

References 29 publications

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“…K m values for midazolam 1Ј-hydroxylase were 2.27 Ϯ 0.18, 0.622 Ϯ 0.025, and 1.53 Ϯ 0.09 M in HLM, rCYP3A4, and rCYP3A5, respectively (Table 7; Fig. 2), consistent with previously reported values of 2.4 to 12 M for liver microsomes (Gascon and Dayer, 1991;Sharer et al, 1995;Ghosal et al, 1996; Transon et al, 1996;Von Moltke et al, 1996b;Maenpaa et al, 1998;Wandel et al, 1998;Wang et al, 1999;Martinez et al, 2000;Warrington et al, 2000;Yin et al, 2000;Hamaoka et al, 2001;Andrews et al, 2002;Li et al, 2003) (Fig. 4), 1.0 to 8.9 M for rCYP3A4 (Ghosal et al, 1996;Gibbs et al, 1999;Eiselt et al, 2001;Khan et al, 2002;Obach and Reed-Hagen, 2002;Williams et al, 2002;Yamaori et al, 2003), and 4.1 to 14 M for rCYP3A5 (Gibbs et al, 1999;Williams et al, 2002;Yamaori et al, 2003).…”

Section: Validated Assays For Human Cytochrome P450 Enzymessupporting

confidence: 80%

Validated Assays for Human Cytochrome P450 Activities

Walsky

Obach²

2004

Drug Metab Dispos

465

380

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ABSTRACT:The measurement of the effect of new chemical entities on human cytochrome P450 marker activities using in vitro experimentation represents an important experimental approach in drug development. In vitro drug interaction data can be used in guiding the design of clinical drug interaction studies, or, when no effect is observed in vitro, the data can be used in place of an in vivo study to claim that no interaction will occur in vivo. To make such a claim, it must be assured that the in vitro experiments are performed with absolute confidence in the methods used and data obtained. To meet this need, 12 semiautomated assays for human P450 marker substrate activities have been developed and validated using approaches described in the GLP (good laboratory practices) as per the code of U.S. Federal Regulations. The assays that were validated are: phenacetin O-deethylase (CYP1A2), coumarin 7-hydroxylase (CYP2A6), bupropion hydroxylase (CYP2B6), amodiaquine N-deethylase (CYP2C8), diclofenac 4-hydroxylase and tolbutamide methylhydroxylase (CYP2C9), (S)-mephenytoin 4-hydroxylase (CYP2C19), dextromethorphan O-demethylase (CYP2D6), chlorzoxazone 6-hydroxylase (CYP2E1), felodipine dehydrogenase, testosterone 6␤-hydroxylase, and midazolam 1-hydroxylase (CYP3A4 and CYP3A5). High-pressure liquid chromatography-tandem mass spectrometry, using stable isotope-labeled internal standards, has been applied as the analytical method. This analytical approach, through its high sensitivity and selectivity, has permitted the use of very low incubation concentrations of microsomal protein (0.01-0.2 mg/ml). Analytical assay accuracy and precision values were excellent. Enzyme kinetic and inhibition parameters obtained using these methods demonstrated high precision and were within the range of values previously reported in the scientific literature. These methods should prove useful in the routine assessments of the potential for new drug candidates to elicit pharmacokinetic drug interactions via inhibition of cytochrome P450 activities.Drug-drug interactions are of great interest to scientists involved in drug research, regulatory authorities who are responsible for public safety, physicians, and their patients. Since "polypharmacy," or the practice of simultaneous prescription of more than one drug to treat one or more conditions in a single patient, has become a more common practice, drug interactions have been cited as one of the major reasons for hospitalization and even death (Lazarou et al., 1998). Thus, a great deal of effort is expended by researchers engaged in new drug research in avoiding the development of compounds that will cause drug-drug interactions.The most common mechanism underlying drug-drug interactions is the inhibition of cytochrome P450 activities. Several drugs in common use cause large increases in exposure to other drugs. Examples include ketoconazole, itraconazole, erythromycin, clarithromycin, diltiazem, and nefazodone (CYP3A); quinidine, paroxetine, and terbinafine (CYP2D6); ticlopidine (CYP2C19); ...

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Section: Validated Assays For Human Cytochrome P450 Enzymessupporting

confidence: 80%

Validated Assays for Human Cytochrome P450 Activities

Walsky

Obach²

2004

Drug Metab Dispos

465

380

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“…Ketoconazole is an inhibitor of several P450s, but is a particular potent inhibitor of CYP3A isoforms with an apparent Ki value of 0.1 gM in human liver microsomes [46]. We found that ketoconazole was a weak inhibitor of all three oxidative pathways of theophylline metabolism, suggesting that CYP3A is not important for the formation of 13DMU.…”

Section: Discussionmentioning

confidence: 67%

Selective serotonin reuptake inhibitors and theophylline metabolism in human liver microsomes: potent inhibition by fluvoxamine.

Rasmussen¹,

Mäenpää²,

Pelkonen³

et al. 1995

Brit J Clinical Pharma

141

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1 Fluvoxamine and seven other selective serotonin reuptake inhibitors (SRRI) were tested for their ability to inhibit a number of human cytochrome P450 isoforms (CYPs). 2 None of the drugs showed potent inhibition of CYP2A6 (coumarin 7-hydroxylase) or CYP2E1 (chlorzoxazone 6-hydroxylase), while norfluoxetine was the only 5 Ethanol inhibited the formation of 1,3-dimethyluric acid with a Ki value of 300 JM, a value which is consistent with inhibition of CYP2E1. Ethanol and fluvoxamine both inhibited 8-hydroxylation by about 45% and, in combination, the compounds decreased the formation of 1,3-dimethyluric acid by 90%, indicating that CYP1A2 and CYP2E1 are equally important isoforms for the 8-hydroxylation of theophylline. 6 It is concluded that pharmacokinetic interaction between fluvoxamine and theophylline is due to potent inhibition of CYP1A2.

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“…Gascon and Dayer (1991) described the kinetics of midazolam with HLMs and also found that formation of 1Ј-hydroxymidazolam and 4Ј-hydroxymidazolam was linear up to 15 min only with HLMs. Product inhibition (1Ј-hydroxymidazolam and/or 4Ј-hydroxymidazolam formation) after 10 min could account for the nonlinearity.…”

Section: Discussionmentioning

confidence: 97%