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LETTER

PREDICTING THE CLEARANCE OF CYP2C9 SUBSTRATES

Simcyp Limited, Blades Enterprise Centre, John Street, Sheffield S2 4SU, United Kingdom (K.R.Y., E.M.H., G.T.T., A.R.-H.); and Academic Unit of Clinical Pharmacology & Therapeutics, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, United Kingdom (G.T.T., A.R.-H.) E-mail: k.r.yeo{at}simcyp.com

(Received August 6, 2004; accepted September 14, 2004)

	Use of fub Instead of fup

Top Use of fub Instead... Metabolism Pathways References

 
Andersson et al. (2004) used the fraction unbound in plasma (fu_p) instead of the fraction unbound in blood (fu_b). It is necessary to use the latter when relating clearance to hepatic blood flow (Rowland and Tozer, 1995). The blood to plasma ratio for fluvastatin was cited to be 1.8, but, in fact, this is the plasma to blood ratio; an independent report confirms this (Tse et al., 1993). If these corrections are applied, three of the four (diclofenac, fluvastatin, and ibuprofen) hepatic blood clearance estimates for the CYP2C9 substrates fall within 2.5-fold of the observed in vivo clearances. In the case of tolbutamide, a low- clearance drug, the predictions are very sensitive to fu_b and fu_p. Therefore, it is important to consider a range of values for these parameters; reported values for fu_p range from 0.02 to 0.084 (Rostami-Hodjegan et al., 1998). Using the weighted mean of 0.056 (and blood to plasma ratio of 0.55), the clearance estimate for tolbutamide now lies within 2.5-fold of the observed clearance. Hepatic clearance estimates of 191, 13, 26, and 449 ml/min were calculated for diclofenac, tolbutamide, ibuprofen, and fluvastatin, respectively.

	Metabolism Pathways

Top Use of fub Instead... Metabolism Pathways References

 
The acyl glucuronidation of diclofenac was not considered in the estimate of its clearance. Kumar et al. (2002) have reported that diclofenac clearance was accurately predicted (within 1.25-fold) only when both acyl glucuronidation and diclofenac 4-hydroxylation were considered. Using the CL_int value of 74,913 ml/min/liver (Kumar et al., 2002) for the combined pathways, in addition to the corrections described above, the hepatic clearance is calculated to be 321 ml/min (within 1.3-fold of the in vivo value).

For ibuprofen, the principal metabolite is 3-hydroxyibuprofen, which is formed mainly by CYP2C9. 2-Hydroxylation is also considered to play a significant role in the metabolism of this drug, yet Andersson et al. (2004) focused only on the 3-hydroxylation pathway for their prediction. Hamman et al. (1997) have reported enzyme kinetic data for both pathways. Using a combined CL_int of 3024 ml/min/liver, in vivo clearance is now estimated at 53 ml/min (within 1.5-fold).

Clearly, the predictions of clearance and drug-drug interaction potential are now compatible when the appropriate calculations are made, and it is unreasonable to question the reliability of in vitro-in vivo extrapolation without adequate in cerebro input.

	Footnotes

 
The authors have no conflicts of interest.

doi:10.1124/dmd.104.001792.

ABBREVIATIONS: CL_int, intrinsic clearance.

	References

Top Use of fub Instead... Metabolism Pathways References

 


Andersson TB, Bredberg E, Ericsson H, and Sjoberg H (2004) An evaluation of the in vitro metabolism data for predicting the clearance and drug-drug interaction potential of CYP2C9 substrates. Drug Metab Dispos 32: 715-721.[Abstract/Free Full Text]

Hamman MA, Thompson GA, and Hall SD (1997) Regioselective and stereoselective metabolism of ibuprofen by human cytochrome P450 2C. Biochem Pharmacol 54: 33-41.[CrossRef][Medline]

Kumar S, Samuel K, Subramanian R, Braun MP, Stearns RA, Chiu LH, Evans DC, and Baillie TA (2002) Extrapolation of diclofenac clearance from in vitro microsomal metabolism data: role of acyl glucuronidation and sequential metabolism of the acyl glucuronide. Drug Metab Dispos 303: 715-721.

Rostami-Hodjegan A, Peacey SR, George E, Heller R, and Tucker GT (1998) Population-based modelling to demonstrate extrapancreatic effects of tolbutamide. Am J Physiol 274: 758-771.

Rowland M and Tozer TN (1995) Clinical Pharmacokinetics: Concepts and Applications, pp 162-167, Lippincott Williams & Wilkins, Philadelphia.

Tse FL, Nickerson DF, and Yardley WS (1993) Binding of fluvastatin to red blood cells and plasma proteins. J Pharm Sci 82: 942-947.[Medline]

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