Role of human CYP3A4 in the biotransformation of sorafenib to its major oxidized metabolites

Ghassabian, Sussan; Rawling, Tristan; Zhou, Fanfan; Doddareddy, Munikumar Reddy; Tattam, Bruce N.; Hibbs, David E.; Edwards, R. J.; Cui, Pei; Murray, Michael T.

doi:10.1016/j.bcp.2012.04.001

Cited by 51 publications

(56 citation statements)

References 44 publications

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“…In addition, most Km values reveal a strong affinity of the TKI-CYP complexes ( Table 2 ; values in the low micromolar range). The determined Km values of TKI for CYP3A4 were compared with available data (differences up to 3×) [15], [23], [24], [25], [26], [27]. Thus, our data confirm the excellent affinity of the studied TEME for dasatinib, imatinib, nilotinib, sorafenib and sunitinib.…”

Section: Discussionsupporting

confidence: 70%

Important Role of CYP2J2 in Protein Kinase Inhibitor Degradation: A Possible Role in Intratumor Drug Disposition and Resistance

et al. 2014

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We have investigated in vitro the metabolic capability of 3 extrahepatic cytochromes P-450, CYP1A1, 1B1 and 2J2, known to be over-expressed in various tumors, to biotransform 5 tyrosine kinase inhibitors (TKI): dasatinib, imatinib, nilotinib, sorafenib and sunitinib. Moreover, mRNA expression of CYP1A1, 1B1, 2J2 and 3A4 in 6 hepatocellular and 14 renal cell carcinoma tumor tissues and their surrounding healthy tissues, was determined.Our results show that CYP1A1, 1B1 and especially 2J2 can rapidly biotransform the studied TKIs with a metabolic efficiency similar to that of CYP3A4. The mRNA expression of CYP1A1, 1B1, 2J2 and 3A4 in tumor biopsies has shown i) the strong variability of CYP expression and ii) distinct outliers showing high expression levels (esp. CYP2J2) that are compatible with high intratumoral CYP activity and tumor-specific TKI degradation.CYP2J2 inhibition could be a novel clinical strategy to specifically increase the intratumoral rather than plasma TKI levels, improving TKI efficacy and extending the duration before relapse. Such an approach would be akin to beta-lactamase inhibition, a classical strategy to avoid antibiotic degradation and resistance.

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Section: Discussionsupporting

confidence: 70%

Important Role of CYP2J2 in Protein Kinase Inhibitor Degradation: A Possible Role in Intratumor Drug Disposition and Resistance

et al. 2014

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“…Biotransformation of sorafenib to the N-oxide is mediated primarily by CYP3A4 (Lathia et al, 2006;Ghassabian et al, 2012). The low formation of sorafenib N-oxide in day 7 human sandwich-cultured hepatocytes may be due to lower cytochrome P450 enzyme activity after isolation and culture (Hoen et al, 2000;Boess et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Sorafenib Hepatobiliary Disposition: Mechanisms of Hepatic Uptake and Disposition of Generated Metabolites

et al. 2013

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Sorafenib is an orally active tyrosine kinase inhibitor used in the treatment of renal and hepatocellular carcinoma. This study was designed to establish whether transport proteins are involved in the hepatic uptake of sorafenib and to determine the extent of biliary excretion of sorafenib and its metabolites in human hepatocytes. Initial uptake was assessed in freshly isolated, suspended human hepatocytes in the presence of inhibitors and modulators. [ OCT inhibitor, 1-methyl-4-phenylpryidinium. OCT1-mediated uptake was saturable with a Michaelis-Menten constant of 3.80 6 2.53 mM and a V max of 116 6 42 pmol/mg/min. The biliary excretion index and in vitro biliary clearance of sorafenib (1 mM) in sandwich-cultured human hepatocytes were low (∼11% and 11 ml/min/kg, respectively). Results suggest that sorafenib uptake in human hepatocytes occurs via passive diffusion, by OCT1, and by organic anion transporting polypeptide(s). Sorafenib undergoes modest biliary excretion, predominantly as a glucuronide conjugate(s).

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“…Sorafenib and its metabolites (N9-hydroxymethylsorafenib N-oxide, sorafenib N-oxide, N9-hydroxymethylsorafenib, N9-desmethylsorafenib, and N9-desmethylsorafenib N-oxide) were synthesized as described previously (Ghassabian et al, 2012). Other MKIs were purchased from Selleck Chemicals (Houston, TX).…”

Section: Methodsmentioning

confidence: 99%

Selective Inhibition of Human Solute Carrier Transporters by Multikinase Inhibitors

et al. 2014

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Solute carrier (SLC) transporters regulate the cellular influx and disposition of endogenous and xenobiotic compounds, including anticancer agents such as the multikinase inhibitors (MKIs). Recent evidence suggests that MKIs may also inhibit SLC-dependent transport of coadministered drugs, although present information on the relative susceptibilities of multiple SLC transporters is limited. This study evaluated 18 MKI drugs and metabolites as inhibitors of prototypic substrate uptake by 13 SLC transporters that were overexpressed in human embryonic kidney cells. Organic anion transporting polypeptides (OATPs) 1A2, 1B3, and 2B1, organic anion transporter 3 (OAT3), and organic cation transporter 1 (OCT1) were inhibited by most MKIs, whereas substrate uptake by OATP1B1, OAT1, 2, and 4, OCT2 and 3, and organic zwitterion/cation transporter 1 (OCTN1) was less susceptible to inhibition; OCTN2 was also inhibited by cediranib. In further studies, IC 50 values were determined for the most effective MKIs, and erlotinib and cediranib were found to be potent competitive inhibitors of OATP2B1 (K i = 41 nM) and OATP1A2 (K i = 33 nM), respectively. From predictive approaches, several MKI-SLC interactions were found to be of potential in vivo significance.

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Role of human CYP3A4 in the biotransformation of sorafenib to its major oxidized metabolites

Cited by 51 publications

References 44 publications

Important Role of CYP2J2 in Protein Kinase Inhibitor Degradation: A Possible Role in Intratumor Drug Disposition and Resistance

Important Role of CYP2J2 in Protein Kinase Inhibitor Degradation: A Possible Role in Intratumor Drug Disposition and Resistance

Sorafenib Hepatobiliary Disposition: Mechanisms of Hepatic Uptake and Disposition of Generated Metabolites

Selective Inhibition of Human Solute Carrier Transporters by Multikinase Inhibitors

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