Covariate modelling, covaraite effects

Dear NMusers, I would like to have your help on the following issue: I am trying to model the PK of a parent compound and two metabolites (M1 is the major and M2 is the minor metabolite), both metabolites are mainly eliminated by renal excetion although a minor biliar excretion pathway exists. Creatinine clearance (CLCR) values in the studied population range form 10 to 100 mL/min. The plots of eta vs CLCR show a relationship in both cases The inclusion of CLCR on CLM1 as covariate decreases significantly the OFV value in 1779 units with respect to the base model, and a decrease of about 30% is observed in the IIV of this parameter (CLM1). In the case of the second metabolite (M2) the inclusion of CLCR on CLM2 decreases the OFV around 700 units but no reduction of IIV of CLM2 is observed when compared with the base model. For the second metabolite, reduction in the residual error with respect to the base model is very low (around 10%). The way I entered the covariates was in both cases TVCL= theta(x)*(CLCR/mean population CLCR value)**(theta(y)). In both cases, all the model parameters were estimated correctly. Then my question is if I should leave CLCR in CLM2 or I should remove it. I would appreciate your comments and suggestions about how to deal with this and about what could be the reasons of this. Best regards joann