RE: protein binding

From: "Anthe Zandvliet" Apaza@SLZ.NL Subject: RE:[NMusers] protein binding Date: Thu, June 24, 2004 12:13 pm Leonid, I agree with you that the differential equation is very remarkable. The addition of the second part results in a first order decrease of the concentration of free drug versus time. I do not think that this corresponds to any physiological explanation. Below I have quoted a colleague (pharmacologist), who explained me very well how clearance of highly bound drugs is dependent of their off rates. In my opinion we should indeed use DADT(1)=-K10*A(2) for drugs with a low off rate. For protein bound drugs with a high off rate, DADT(1)=-K10*A(1) seems a better choice. Furthermore, the message ERROR IN LSODI1: CODE 204 keeps bothering me, but replacement of A(2)=A(1)-A(3) with A(2)=0.5*(((KD+BMAX-A(1))**2+4*KD*A(1))**0.5-(KD+BMAX-A(1))) seems to be a major improvement. Finally, it is essential to use the above expression in the differential equation as well: wrong: DADT(1)=-K10*A(2) right: DADT(1)=-K10*(0.5*(((KD+BMAX-A(1))**2+4*KD*A(1))**0.5-(KD+BMAX-A(1)))) This is important because the $AES equations are solved only at the time points listed in the dataset, which will lead to a stepwise outcome of the $DES function if the wrong expression is used. Does anyone have additional suggestions how to get rid of the LSODI1 error messages? Thanks! Anthe PROTEIN BINDING The effect of protein binding seems to be more complex than the model suggests. For example, the KD is a function of 'on' and 'off' rates. The ratio of these rates (KD) affects the % bound as a function of concentration, but these on/off rates also determine the time taken to reach equilibrium and the susceptibility to clearance. For example, some highly bound drugs are protected from clearance because they are highly bound (here the off rate is low compared to transit time in clearing organ), whereas some very highly bound drugs have high clearance (off time is rapid compared to transit time). Hence, it's not KD that's so important but the actual magnitude of the on/off rates. Thus, clearance may not be limited to free drug in a sense and some highly bound drugs may be cleared by liver with a clearance approximating liver blood flow - of course only free drug is actually cleared but the rapid exchange between bound/free enables the bound drug to be effectively available for clearance. Thus, where off rate is sufficiently high, clearance will be first order regardless of the % bound/concentration but where off rate is slow, clearance of total drug (bound and unbound) will be non-linear in the fashion you describe (ie low clearance at low concs due to high binding and high clearance at high concs due to relatively high fraction unbound and available for clearance).