Probe drugs

Figure 7.21 Structures of probe drugs used in the PAMPA models.

Hartter, S., Ursing, C., Morita, S., Tybring, G. et al. (2001). Orally given melatonin may serve as a probe drug for cytochrome P450 1A2 activity in vivo a pilot study. Clin. Pharmacol. Ther. 70, 10-16. 

The QSAR (4) cannot only highlight structural factors most likely to impact positively or negatively upon their biological activity, it can be used to probe drug-DNA interactions. QSAR (4) has already enabled identification of candidates with reasonable anticancer activity and can direct future synthesis and design to this end. 

Spaldin, V., Madden, S., Adams, D.A., Edwards, R.J., Davies, D.S. and Park, B. K. (1995) Determination of human hepatic cytochrome P4501A2 activity in vitro use of tacrine as an isoenzyme-specific probe. Drug Metabolism and Disposition, 23 (9), 929-934. 

Jondorf WR. Drug metabolism as evolutionary probes. Drug Metab Rev 1981 12 379. 

Kossena, G. A., W. N. Charman, B. J. Boyd, D. E. Dunstan, and C. J. H. Porter. 2004. Probing drug solubilization patterns in the gastrointestinal tract after administration of lipid-based delivery systems A phase diagram approach).. Pharm. Sci93 332-348. 

Critical to the success of this screening approach is the selection and use of probe substrates that have a specific metabolic pathway mediated by a single CYP. An example of specific CYP probe substrates initially studied by Dear and co-workers (Ayrton et al., 1998a) is shown in Table 6.9. Many laboratories conduct detailed validation of CYP probe substrates to determine whether they can be simultaneously administered without metabolic interaction. One metabolic cocktail consists of the probe drugs caffeine, chlorzoxazone, dapsone, debrisoquin, and mephenytoin and is referred to as the Pittsburgh cocktail (Frye et al., 1997). The use of LC/MS/MS allows for the rapid... 

Brynne N, Bottiger Y, Hallen B, Bertilsson L. Tolterodine does not affect the human in vivo metabolism of the probe drugs caffeine, debrisoquine and omeprazole. Br J Clin Pharmacol 1999 47 145-150. 

The phenotype for human CYP1A2 activity can be conveniently measured in vivo using caffeine as a probe drug and measuring urinary or salivary metabolite profiles. The caffeine metabolic ratio is increased in populations of smokers (31,92) and wide ranges of CYP1A2 activity have been measured in many different human studies (Table 2). 

Zhang Z, Fasco MJ, Huang Z, et al. Human cytochromes P4501A1 and P4501A2— R-warfarin metabolism as a probe. Drug Metab Dispos 1995 23 1339-1345. 

The urinary MR should provide similar information to that of the ratio of the plasma AUC values of the in vivo probe drug and metabolite over the collection time period, but it has the practical advantage of a single urine collection, compared with multiple plasma samples. In order to simplify a plasma-based trait measure, the plasma concentration ratio of metabolite to unchanged dmg at a single time point after drug administration has also been used, e.g., plasma 6-hydroxychlorzoxazone chlorzoxazone ratio as a measure of CYP2E1 activity... 

By probing drug treated cells for expression of genes and proteins it may be possible to more precisely identify the specific mode of action of a drag of known therapeutic value, for example natural herbal remedies, thereby offering opportunities to develop new drags for such therapeutic conditions. 

Probe drugs used for CYP2C9 phenotyping are tolbutamide, S-warfarin, phenytoin and losartan. Diclofenac, flurbiprofen, phenprocoumone and torasemide have also been used. For safety concerns, the current preferred probe is tolbutamide, despite some risk of hypoglycemia. 

Probe drugs used for CYP2C19 phenotyping are mephenytoin, omeprazole and proguanil. The most currently used probe drug is omeprazole. 

Omeprazole hydroxylation rate correlates with S-mephenytoin hydroxylation rate, which was initially the CYP2C19 probe drug (Andersson 1990 Chang 1995 Balian 1995). The alternate pathway - conversion of omeprazole to its sulfone derivative -, which is mediated via CYP3A4, does not influence the CYP2C19 pathway of omeprazole (Balian 1995). 

The most used and validated probe drugs for C YP3 A phenotyping are midazolam and 14C-erythromycin (Watkins 1994). Alfentanyl, alprazolam, dapsone, dextromethorphan, lidocaine. nifedipine, omeprazole, quinine, verapamil have also been used but less frequently, and CYP3A specificity for some of them has been questioned. The endogenous 6(->-hydroxycortisol test (measurement of 6 3-hydroxycortisol cortisol ratio in urine) is only useful for detecting CYP3A induction, and may be influenced by renal CYP3 A activity. 

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