Drug interaction prediction using ontology-driven hypothetical assertion framework for pathway generation followed by numerical simulation

Table 4 Kinetic parameters for metabolic enzymes.

Enzyme	Substrate	Product	K_m[μ M]	V_max[pmol/min/mg protein]	α[mg protein/g tissue]	V_max·α/K_m[mL/min/g tissue]
Carboxylesterase	Irinotecan	SN-38	2.30	2.11	128	0.117
Carboxylesterase	NPC	SN-38	2.30	2.11	128	0.117
CYP3A4	Irinotecan	APC	18.4	26.0	73.3	0.104
CYP3A4	Irinotecan	NPC	48.2	74.1	11.7	0.0180
UGT1A1	SN-38	SN-38G	3.80	50.8	750	10.0
CYP3A4	KCZ	MOK	0.00810	12.5	44.3	68.4

Because of the lack of experimental data, K_mand V_maxvalues for metabolism of NPC to SN-38 by CE were assumed to be the same as those for metabolism of irinotecan to SN-38 by CE. K_mand V_maxvalues for other reactions were obtained from the published papers [25–29]. Values of unknown parameter α were determined so that the simulation concentration/time profile fit to the experimental data published by Slatter et al. [18]. The relatively high fitted value for α in the glucronidation of SN-38 may result from the increase in UGT1A1 expression as drug response. The relatively low value for α in the oxidation of irinotecan to NPC by CYP3A4 suggests a competition in this reaction with the oxidation of irinotecan to APC by CYP3A4.

ISSN: 1471-2105