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. 2010 Dec;70(6):844-53.
doi: 10.1111/j.1365-2125.2010.03789.x.

The combined impact of CYP2C19 and CYP2B6 pharmacogenetics on cyclophosphamide bioactivation

Nuala A Helsby  1 , Chung-Yee Hui, Michael A Goldthorpe, Janet K Coller, May Ching Soh, Peter J Gow, Janak Z De Zoysa, Malcolm D Tingle
Affiliations

The combined impact of CYP2C19 and CYP2B6 pharmacogenetics on cyclophosphamide bioactivation

Nuala A Helsby et al. Br J Clin Pharmacol. 2010 Dec.

Abstract

Aims: The role of CYP pharmacogenetics in the bioactivation of cyclophosphamide is still controversial. Recent clinical studies have suggested a role for either CYP2C19 or CYP2B6. The aim of this study was to clarify the role of these pharmacogenes.

Methods: We used a combined in vitro-in vivo approach to determine the role of these pharmacogenes in the bioactivation of the prodrug to 4-hydroxy cyclophosphamide (4-OHCP). Cyclophosphamide metabolism was determined in a human liver biobank (n= 14) and in patients receiving the drug for treatment of lupus nephritis (n= 16)

Results: In livers of known CYP2C19 and CYP2B6 genotype and protein expression we observed that there was a combined role for both CYP2C19 and CYP2B6 in the bioactivation of cyclophosphamide in vitro. The presence of at least one loss of function (LoF) allele at either CYP2C19 or CYP2B6 resulted in a significant decrease in both V(max) (P= 0.028) and CL(int) (P= 0.0017) compared with livers with no LoF alleles. This dual genotype relationship was also observed in a preliminary clinical study, with patients who had ≥1 LoF allele at either CYP2C19 or CYP2B6 also displaying significantly (P= 0.0316) lower bioactivation of cyclophosphamide. The mean 4-OHCP : CP bioactivation ratio was 0.0014 (95% CI 0.0007, 0.002) compared with 0.0071 (95% CI 0.0001, 0.014) in patients with no LoF alleles at either of these genes.

Conclusions: The presence of ≥1 LoF allele(s) at either CYP2B6 or CYP2C19 appeared to result in decreased bioactivation of cyclophosphamide both in vitro and in patients. Further clinical studies to confirm this relationship are warranted.

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Figures

Figure 1
Figure 1
Formation of 4-hydroxy cyclophosphamide (4-OH CP) from cyclophosphamide (0.25–20 mm) by human liver microsomes in vitro. Examples of livers with high (circles), intermediate (triangles) and low (squares) metabolic capacity are shown. Data shown as the mean ± SD of triplicate determinations
Figure 2
Figure 2
The relationship between CYP2C19 and CYP2B6 genotype, protein expression and cyclophosphamide bioactivation (intrinsic clearance) in the Auckland human liver bank. Spearman rank order correlation (rs) of protein expression vs. intrinsic clearance is shown (C) and (D)
Figure 3
Figure 3
The role of the combined CYP2C19 and CYP2B6 genotype in the bioactivation of cyclophosphamide in vitro by human liver. aThis liver has no functional CYP2C19 activity
Figure 4
Figure 4
The relationship between decreased bioactivation of cyclophosphamide (A) in vitro and (B) in vivo and the presence of at least one (≥1) loss of function (LoF) allele at either CYP2C19 and CYP2B6. A) Presence of one or more LoF alleles at either CYP2C19 or CYP2B6 results in a significant (P = 0.0017, t = 4.03, d.f. 12) decrease in intrinsic clearance compared with livers that have zero LoF alleles at these genes. (B) Presence of one or more LoF alleles at either CYP2C19 or CYP2B6 results in a significant (P = 0.0316, t = 2.43, d.f. 12) decrease in bioactivation ratio compared with patients that have zero LoF alleles at these genes
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