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Multiple Inhibition Mechanisms and Prediction of Drug–Drug Interactions: Status of Metabolism and Transporter Models as Exemplified by Gemfibrozil–Drug Interactions

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Purpose

To assess the consequences of multiple inhibitors and differential inhibition mechanisms on the prediction of 12 gemfibrozil drug–drug interactions (DDIs). In addition, qualitative zoning of transporter-related gemfibrozil and cyclosporine DDIs was investigated.

Methods

The effect of gemfibrozil and its acyl-glucuronide on different enzymes was incorporated into a metabolic prediction model. The impact of CYP2C8 time-dependent inhibition by gemfibrozil acyl-glucuronide was assessed using repaglinide, cerivastatin, loperamide, rosiglitazone and pioglitazone DDIs. Gemfibrozil and cyclosporine inhibition data obtained in human embryonic kidney cells expressing OATP1B1 and hepatic input concentration ([I]in) were used for qualitative zoning of 14 transporter-mediated DDIs.

Results

Incorporation of time-dependent inhibition by gemfibrozil glucuronide showed no significant improvement in the prediction, as CYP2C8 contributed <65% to the overall elimination of the victim drugs investigated. Qualitative zoning of OATP1B1 DDIs resulted in no false negative predictions; yet the magnitude of observed interactions was significantly over-predicted.

Conclusions

Time-dependent inhibition by gemfibrozil glucuronide is only important for victim drugs eliminated predominantly (>80%) via CYP2C8. Qualitative zoning of OATP1B1 inhibitors based on [I]in/K i is valid in drug screening to avoid false negatives. Refinement of the transporter model by incorporating the fraction of drug transported by a particular transporter is recommended.

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Abbreviations

AUC:

area under the plasma concentration–time curve

AUCi:

area under the curve in the presence of the inhibitor

DDI:

drug–drug interactions

fmCYPi :

fraction of drug metabolised by the particular P450 enzyme subject to inhibition

F+, F−:

false positive and false negative predictions

ft:

the fraction of drug transported by a particular transporter protein

[I]:

inhibitor concentration

[I]in:

hepatic input concentration

K I :

inhibitor concentration at 50% of k inact

K i :

inhibition constant

k deg :

enzyme degradation rate constant

k inact :

maximal inactivation rate constant

TDI:

time-dependent inhibition

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Acknowledgement

The authors would like to thank Dr Kathryn Kenworthy and Mrs Jennifer Thomas (GlaxoSmithKline, Ware, UK) for their help with the OATP1B1 inhibition assay.

The work was funded by a consortium of pharmaceutical companies (GlaxoSmithKline, Lilly, Novartis, Pfizer and Servier) within the Centre for Applied Pharmacokinetic Research at the University of Manchester. Part of this study was presented at the 9th ISSX Meeting, June 4–7, 2006, Manchester, UK.

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Correspondence to Aleksandra Galetin.

Appendix

Appendix

Total hepatic clearance can be described by Eq. 7 (58,61,62):

$$ {\text{CL}}_{{\operatorname{int} ,{\text{all}}}} = {\text{PS}}_{{\inf \,{\text{lux}}}} \times \frac{{{\text{CL}}_{{\operatorname{int} }} }} {{{\text{PS}}_{{{\text{efflux}}}} + {\text{CL}}_{{\operatorname{int} }} }}$$
(7)

where PSinflux and PSefflux are the membrane permeability–surface area products of a drug across the sinusoidal membrane, for the influx and efflux processes, respectively, and CLint is the intrinsic clearance representing both metabolic and biliary excretion of the drug. When PSefflux << CLint, CLint,all = PSinflux. PSinflux can also be described as the clearance due to influx into the cell (CLinflux) (62).

When the uptake of a drug involves more than one transporter, the total influx clearance can be defined as the sum of the ratios of the Michaelis–Menten parameters for the individual transporters, assuming linear kinetics (substrate concentration <<K m), as shown in Eq. 8:

$$ {\text{CL}}_{{{\text{influx}}}} = \frac{{V_{{{\text{max}}1}} }} {{K_{{{\text{m}}1}} }} + \frac{{V_{{{\text{max}}2}} }} {{K_{{{\text{m}}2}} }} = {\text{ft}}_{{{\text{OATP1B1}}}} {\text{CL}}_{{{\text{influx}}}} + {\left( {1 - {\text{ft}}_{{{\text{OATP1B1}}}} } \right)} {\text{CL}}_{{{\text{influx}}}} $$
(8)

where 1 and 2 refer to influx via a particular transporter (e.g., OATP1B1). The term ftOATP1B1 refers to the fraction of the drug transported by way of the OATP1B1 transporter, whereas the remaining fraction is transported by unspecified routes.

Influx clearance in the presence of a competitive inhibitor of OATP1B1 (CLinflux i ) or 2 inhibitors acting via the same mechanism is shown in Eqs. 9 and 10, respectively:

$$ {\text{CL}}_{{influx}} i = \frac{{V_{{{\text{max1}}}} }} {{K_{{{\text{m}}1}} {\left( {1 + {{\left[ I \right]}} \mathord{\left/ {\vphantom {{{\left[ I \right]}} {K_{i} }}} \right. \kern-\nulldelimiterspace} {K_{i} }} \right)}}} + \frac{{V_{{{\text{max}}2}} }} {{K_{{{\text{m}}2}} }}$$
(9)
$$ {\text{CL}}_{{{\text{influx}}}} i = \frac{{V_{{{\text{max}}1}} }} {{K_{{{\text{m}}1}} {\left( {1 + {{\left[ I \right]}} \mathord{\left/ {\vphantom {{{\left[ I \right]}} {K_{{i1}} }}} \right. \kern-\nulldelimiterspace} {K_{{i1}} } + {{\left[ I \right]}} \mathord{\left/ {\vphantom {{{\left[ I \right]}} {K_{{i2}} }}} \right. \kern-\nulldelimiterspace} {K_{{i2}} }} \right)}}} + {\left( {1 - {\text{ft}}_{{{\text{OATP1B1}}}} } \right)}{\text{ CL}}_{{{\text{influx}}}} $$
(10)

Combining Eqs. 8 and 10 gives:

$$ {\text{CL}}_{{{\text{influx}}}} i = \frac{{{\text{ft}}_{{{\text{OATP1B1}}}} \,{\text{CL}}_{{{\text{influx}}}} }} {{1{\text{ + }}{\sum\limits_j^n {{{\left[ I \right]}j} \mathord{\left/ {\vphantom {{{\left[ I \right]}j} {Ki,j}}} \right. \kern-\nulldelimiterspace} {Ki,j}} }}} + {\left( {1 - {\text{ft}}_{{{\text{OATP1B1}}}} } \right)}{\text{CL}}_{{{\text{influx}}}} $$
(11)

Assuming competitive inhibition and that the other transport processes are unaffected by the inhibitor, the AUC ratio is given by the following equation:

$$ \frac{{{\text{AUC}}i}} {{{\text{AUC}}}} = \frac{{{\text{CL}}_{{{\text{influx}}}} }} {{{\text{CL}}_{{{\text{influx}}}} i}} = \frac{1} {{\frac{{{\text{ft}}_{{{\text{OATP1B1}}}} }} {{1 + {\sum\limits_j^n {{{\left[ I \right]}j} \mathord{\left/ {\vphantom {{{\left[ I \right]}j} {Ki,j}}} \right. \kern-\nulldelimiterspace} {Ki,j}} }}} + {\left( {1 - {\text{ft}}_{{{\text{OATP1B1}}}} } \right)}}}$$
(12)

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Hinton, L.K., Galetin, A. & Houston, J.B. Multiple Inhibition Mechanisms and Prediction of Drug–Drug Interactions: Status of Metabolism and Transporter Models as Exemplified by Gemfibrozil–Drug Interactions. Pharm Res 25, 1063–1074 (2008). https://doi.org/10.1007/s11095-007-9446-6

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