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Marker Substrates. CLint values were obtained for each of the prototypic substrates, tolbutamide, diazepam, metoprolol, ibuprofen, propranolol, dextromethorphan, omeprazole, diltiazem, testosterone, and verapamil in three individual preparations of pooled HLM. Table 3 compares the CLint for the three batches of HLM together with the mean and values obtained from the literature. For substrates with significant CYP3A4 metabolism, diltiazem, testosterone, and verapamil, CLint was significantly higher in batch 1 compared with batches 2 and 3. The coefficient of variation was generally int determined from one pool of HLM.
To investigate the relationship between the CLint of propranolol with increasing HLM protein concentration, CLint was determined at 0.4, 1, and 2 mg · ml1 of HLM. Figure 3 shows the relationship between increasing microsomal protein and decreasing CLint of propranolol.
The metabolite profile for the CYP-dependent clearance of dextromethorphan observed by HPLC-mass spectrometry was as predicted from Von Moltke et al. (1998), where microsomes containing individual CYPs expressed by a human lymphoblastoid expression system were used (Fig. 4). Dextromethorphan was chosen for this detailed analysis, because four of the five major human CYPs (CYP2C9, -2C19, -2D6, and -3A4) have been implicated in its metabolism. Dextromethorphan was incubated at 30 µM with all five isoforms, and as expected, two metabolites, dextrorphan and 3-methoxymorphinan, were observed, based on their m/z values and distinguished using standards. Based on UV response, 88% of the metabolites formed from dextromethorphan (m/z = 272) were dextrorphan (m/z = 258) and 12% were 3-methoxymorphinan (m/z = 258), which compares well with Von Moltke et al. (1998) (98 and 2%, respectively). The isoform responsible for dextrorphan formation was primarily CYP2D6 (92% versus 97%; as determined from Von Moltke et al., 1998) with minor contributions from CYP2C9, -2C19, and -3A4 ( for 3-methoxymorphinan formation were CYP2C9 (43% versus 55%), CYP3A4 (42% versus 20%), CYP2C19 (8% versus 16%), and CYP2D6 (7% versus 9%). In addition, it was also determined that CYP1A2 metabolized propranolol (m/z = 260) to the expected N-deisopropylation product (m/z = 218) (Yoshimoto et al., 1995) and CYP2D6 metabolized propranolol to the expected hydroxylated product (m/z = 276), although the regiochemistry of hydroxylation was not investigated. Several other markers also generated the product profile as expected from the literature (data not shown).
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