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Population Pharmacokinetic Modeling of trans-Resveratrol and Its Glucuronide and Sulfate Conjugates After Oral and Intravenous Administration in Rats

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ABSTRACT

Purpose

To develop a population pharmacokinetic (PK) model which allowed the simultaneous modeling of trans-resveratrol and its glucuronide and sulfate conjugates.

Methods

Male Sprague–Dawley rats were administered i.v. and p.o. with 2, 10 and 20 mg·kg−1 of trans-resveratrol. Blood was collected at different times during 24 h. An integrated PK model was developed using a sequential analysis, with non-linear mixed effect modeling (NONMEM). A prediction-corrected visual predictive check (pcVPC) was used to assess model performance. The model predictive capability was also evaluated with simulations after the i.v. administration of 15 mg·kg−1 that were compared with an external data set.

Results

Disposition PK of trans-resveratrol and its metabolites was best described by a three-linked two-compartment model. Clearance of trans-resveratrol by conversion to its conjugates occurred by a first-order process, whereas both metabolites were eliminated by parallel first-order and Michaelis-Menten kinetics. The pcVPC confirmed the model stability and precision. The final model was successfully applied to the external data set showing its robustness.

Conclusions

A robust population PK model has been built for trans-resveratrol and its glucuronide and sulfate conjugates that adequately predict plasmatic concentrations.

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Abbreviations

ABC:

ATP-binding cassette

AIC:

Akaike information criterion

AUC:

area under the curve

BCRP:

breast cancer resistance protein

DV:

observed concentrations

IAV:

inter-animal variability

IPRED:

individual model predicted concentrations

MRP:

multidrug resistance protein

OFV:

objective function value

pcVPC:

prediction corrected visual predictive check

PD:

pharmacodynamic

PK:

pharmacokinetic

PRED:

population model predicted concentrations

RSE:

relative standard error

UGT:

UDP-glucuronosyltransferase

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ACKNOWLEDGMENTS

This study was supported by the Ministerio de Ciencia y Tecnología grants AGL2005-05728 and AGL2009-12866 and the Generalitat de Catalunya grants 2005-SGR-00632 and 2009-SGR-00471.

Author information

Authors and Affiliations

  1. Departament de Farmàcia i Tecnologia Farmacèutica Facultat de Farmàcia, Universitat de Barcelona, Av. Joan XXIII s/n, 08028, Barcelona, Spain

    Helena Colom

  2. Departament de Fisiologia, Facultat de Farmàcia Institut de Recerca en Nutrició i Seguretat Alimentària (INSA-UB), Universitat de Barcelona, Barcelona, Spain

    Irene Alfaras, Mònica Maijó, M. Emília Juan & Joana M. Planas

Authors
  1. Helena Colom
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  2. Irene Alfaras
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  3. Mònica Maijó
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  4. M. Emília Juan
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  5. Joana M. Planas
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Corresponding author

Correspondence to Helena Colom.

APPENDIX

APPENDIX

The NONMEM code used in the final model

Modeling of Intravenous Data

$PROBLEM trans-resveratrol and its conjugates plasmatic concentrations

$INPUT ID TIME AMT DV MDV EVID CMT WGT ROUT DOSA;DOSA=ACTUAL DOSE

$DATA data.csv IGNORE=#

IGNORE (ROUT.EQ.2)

$SUBROUTINES ADVAN6 TOL=3

$MODEL

COMP = (CENTRALRESV,DEFOBS)

 

COMP = (PERIPHRESV)

 

COMP = (CENTRALGLUC)

 

COMP = (PERIPHGLUC)

 

COMP = (CENTRALSULF)

 

COMP = (PERIPHSULF)

 

$PK

 

;DISPOSITION PARAMETERS

 

;trans-Resveratrol

  

TVCL1

= THETA(1)

 

CL1

= TVCL1*EXP(ETA(1))

;Plasmatic CL of resveratrol

V1

= THETA(2)

;Central compartment V of resveratrol

Q

= THETA(3)*EXP(ETA(2))

;Distributional CL of resveratrol

V2

= THETA(4)

;Peripheral compartment V of resveratrol

;Glucuronide

  

V3

= 0.05

;Central compartment V of the glucuronide

QM1

= THETA(5)

;Distributional CL of the glucuronide

V4

= THETA(6) *EXP(ETA(3))

;Peripheral compartment V of the glucuronide

;Linear elimination process

  

CL2

= THETA(7)

;Plasmatic CL of the glucuronide

;Non-linear elimination process

  

VMG

= THETA(8)

;Maximal elimination rate of the glucuronide

KMG

= THETA(9)

;Concentration of the glucuronide at which the elimination is half maximal

FM

= THETA(10)

;Fraction of resveratrol converted to its glucuronide

;Sulfate

  

V5

= THETA(11)

;Central compartment V of the sulfate

V6

= THETA(12)

;Peripheral compartment V of the sulfate

QM2

= THETA(13)

;Distributional CL of the sulfate

;Linear elimination process

  

CL3

= THETA(14)

;Plasmatic CL of the sulfate

;Non-linear elimination process

  

VMS

= THETA(15)

;Maximal elimination rate of the sulfate

KMS

= THETA(16)

;Concentration of the sulfate at which the elimination is half maximal

S1 = V1

S3 = V3

S5 = V5

;RATE CONSTANTS

K12 = Q/V1

K21 = Q/V2

K30 = CL2/V3

K34 = QM1/V3

K43 = QM1/V4

K56 = QM2/V5

K65 = QM2/V6

K50 = CL3/V5

;DIFFERENTIAL EQUATIONS

$DES

DADT(1)

= −K12*A(1)+K21*A(2)-(CL1/V1)*FM*A(1)-(CL1/V1)*(1-FM)*A(1)

DADT(2)

= K12*A(1)-K21*A(2)

DADT(3)

= (CL1/V1)*FM*A(1)-K30*A(3) + K43*A(4)-K34*A(3)-(VMG*A(3))/(KMG + A(3))

DADT(4)

= K34*A(3)-K43*A(4)

DADT(5)

= (CL1/V1)*(1-FM)*A(1)-K56*A(5) + K65*A(6)-K50*A(5))-(VMS*A(5))/(KMS + A(5))

DADT(6)

= K56*A(5)-K65*A(6)

;RESIDUAL ERROR FOR LOG-TRANSFORMED DATA

$ERROR

IPRED

= −5

IF(F.GT.0)

IPRED= LOG(F)

IF(CMT.EQ.2)

Y= IPRED + EPS(1)

IF(CMT.EQ.4)

Y= IPRED + EPS(2)

IF(CMT.EQ.6)

Y= IPRED + EPS(3)

IWRES

= (DV-IPRED)

;INITIAL ESTIMATES

$THETA

$OMEGA

$SIGMA

$ESTIMATION

$COVARIANCE

Modeling of Oral Data

$PROBLEM trans-resveratrol and its conjugates plasmatic concentrations

$INPUT ID TIME AMT DV MDV EVID CMT WGT ROUT DOSA;DOSA=ACTUAL DOSE

$DATA data.csv IGNORE=#

IGNORE (ROUT.EQ.1)

$SUBROUTINES ADVAN6 TOL=3

$MODEL

COMP = (DEPOT)

COMP = (CENTRALRESV,DEFOBS)

COMP = (PERIPHRESV)

COMP = (CENTRALGLUC)

COMP = (PERIPHGLUC)

COMP = (CENTRALSULF)

COMP = (PERIPHSULF)

$PK

“FIRST

“ COMMON/PRCOMG/IDUM1,IDUM2,IMAX,IDUM4,IDUM5

“ INTEGER IDUM1,IDUM2,IMAX,IDUM4,IDUM5

“ IMAX=70000000

;DISPOSITION PARAMETERS

;trans-Resveratrol

  

TVCL1

= THETA(1)

 

CL1

= TVCL1*EXP(ETA(1))

;Plasmatic CL of resveratrol

V2

= THETA(2)

;Central compartment V of resveratrol

Q

= THETA(3)*EXP(ETA(2))

;Distributional CL of resveratrol

V3

= THETA(4)

;Peripheral compartment V of resveratrol

;Glucuronide

  

V4

= 0.05

;Central compartment V of the glucuronide

QM1

= THETA(5)

;Distributional CL of the glucuronide

V5

= THETA(6) *EXP(ETA(3))

;Peripheral compartment V of the glucuronide

FM

= THETA(7)

;Fraction of resveratrol converted to its glucuronide

;Linear elimination process

  

CL2

= THETA(8)

;Plasmatic CL of the glucuronide

;Non-linear elimination process

  

VMG

= THETA(9)

;Maximal elimination rate of the glucuronide

KMG

= THETA(10)

;Concentration of the glucuronide at which the elimination is half maximal

;Sulfate

  

V6

= THETA(11)

;Central compartment V of the sulfate

V7

= THETA(12)

;Peripheral compartment V of the sulfate

QM2

= THETA(13)

;Distributional CL of the sulfate

;Linear elimination process

  

CL3

= THETA(14)

;Plasmatic CL of the sulfate

;Non-linear elimination process

  

VMS

= THETA(15)

;Maximal elimination rate of the sulfate

KMS

= THETA(16)

;Concentration of the sulfate at which the elimination is half maximal

;ABSORPTION PARAMETERS

KA1

= THETA(17)

;Absorption rate constant

KA2

= THETA(18)

;Transformation (from the parent compound to the glucuronide)/Absorption rate constant

TVF1

= THETA(19)*(1-THETA(20)*DOSA)

 

F1

= TVF1*EXP(ETA(4))

;Bioavailability

;SCALE FACTORS

S2 = V2

S4 = V4

S6 = V6

;RATE CONSTANTS

K23 = Q/V2

K32 = Q/V3

K40 = CL2/V4

K45 = QM1/V4

K54 = QM1/V5

K67 = QM2/V6

K76 = QM2/V7

K60 = CL3/V6

;DIFFERENTIAL EQUATIONS

$DES

DADT(1)

= −KA1*F1*A(1)-KA2*(1-F1)*A(1)

DADT(2)

= KA1*F1*A(1)-K23*A(2)+K32*A(3)-(CL1/V2)*FM*A(2)-(CL1/V2)*(1-FM)*A(2)

DADT(3)

= K23*A(2)-K32*A(3)

DADT(4)

= KA2*(1-F1)*A(1)+(CL1/V2)*FM*A(2)-K40*A(4)+K54*A(5)-K45*A(4)-(VMG*A(4))/(KMG+A(4))

DADT(5)

= K45*A(4)-K54*A(5)

DADT(6)

= (CL1/V2)*(1-FM)*A(2)-K67*A(6)+K76*A(7)-K60*A(6))-(VMS*A(6))/(KMS+A(6))

DADT(7)

= K67*A(6)-K76*A(7)

;RESIDUAL ERROR FOR LOG-TRANSFORMED DATA

$ERROR

IPRED

= −5

 

IF(F.GT.0)

IPRED

= LOG(F)

IF(CMT.EQ.2)

Y

= IPRED+EPS(1)

IF(CMT.EQ.4)

Y

= IPRED+EPS(2)

IF(CMT.EQ.6)

Y

= IPRED+EPS(3)

IWRES

= (DV-IPRED)

 

;INITIAL ESTIMATES

$THETA

$OMEGA

$SIGMA

$ESTIMATION

$COVARIANCE

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Colom, H., Alfaras, I., Maijó, M. et al. Population Pharmacokinetic Modeling of trans-Resveratrol and Its Glucuronide and Sulfate Conjugates After Oral and Intravenous Administration in Rats. Pharm Res 28, 1606–1621 (2011). https://doi.org/10.1007/s11095-011-0395-8

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  • DOI: https://doi.org/10.1007/s11095-011-0395-8

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