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Methods and Principles in Medicinal Chemistry - Mannhold R.

Mannhold R., Kubinyi H., Timmerman H. Methods and Principles in Medicinal Chemistry - Wiley-VCH, 2001. - 155 p.
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The exosite appears to be located at the interface of the cytoplasm and the transmembrane domain of the p2-adrenergic receptor [10]. The structures of salbutamol and salmeterol are clearly different, although it is obvious both are based on the “adrenalin” pharmacophore. More subtle changes in structure leading to “slow-offset” can only be rationalized by changes in intra-receptor binding. Possibilities for such increases can include simply increased interaction per se and resultant affinity, with an effect largely confined to changes in the off rate. Thus, telenzepine is more potent than pirenzepine as well as showing slow offset from the receptor [11]. This increase in affinity may simply reflect the increased lipophilicity of the telenzepine head group (Figure 2.14).
It is possible to achieve slow offset without a change in potency. Here conformational restriction may be the mechanism. If one assumes a number of binding functions in a molecule, and that for stable binding all have to interact, then probability suggests that in a flexible molecule, association and disassociation will be occurring rapidly (fast on, fast off). With a molecule whose confirmation is restricted to one favourable to the interactions, it is likely that the rate of association and dissociation will be markedly lower (slow on, slow off). Such restrictions may be very simple molecular changes, for instance a single methyl group converts the fast offset compound carfentanil [12] to the slow offset compound lofentanil (Figure 2.15).
/ I Fig. 2.14 Structures of
pirenzepine and its more CH3 potent, slow offset Ml
antimuscarinic analogue telenzepine telenzepine.
2.12 Factors Governing Unbound Drug Concentration 31


Fig. 2.15 Structures of opioid agonists carfentanil and its slow offset analogue lofentanil.
Factors Governing Unbound Drug Concentration
We thus have in many cases only two parameters defining drug activity at steady state, receptor affinity and free (unbound) plasma concentration. Occasionally actual persistence at the receptor needs to be taken into account. In some cases, particularly hydrophilic drugs, there is a permeation factor that needs to be defined. The concept of steady state allows simplification of the equations and concepts of pharmacokinetics. Steady state in the context here implies a drug dosed at specific times so that the concentrations between administered doses are effectively an exact image of previous doses and that the difference between the peak and trough levels are small. The factors governing the steady state free plasma concentration Cpf for an oral drug, are the dosing rate (dose size x frequency), the fraction of the dose absorbed (F) through the g.i. tract and the free drug clearance (Clu) as shown below:
at steady state: rate in = rate out
(Dose size frequency) • F = Cpf • Clu (2.22)
True steady state is usually only achieved for a prolonged period with intravenous infusion. If we assume that we wish for a similar steady value after oral administration, then we need to balance our dosing frequency with the rate of decline of drug concentration and the rule of thumb referred to earlier (dosing interval equal to drug half-life) can be applied. Unbound clearance and free drug are particularly applicable to drugs delivered by the oral route. For a well-absorbed compound the free plasma concentrations directly relate to Cliu (intrinsic unbound clearance).
This simplifies greatly the concepts of first-pass hepatic metabolism and systemic clearance referred to previously. Most importantly Cliu is directly evolved from the enzyme kinetic parameters, Vmax and Km:
AUC = Dose/Cliu
32 2 Pharmacokinetics
When the drug concentrations are below the Km, Cliu is essentially independent of drug concentration. The processes of drug metabolism are similar to other enzymatic processes. For instance most oxidative processes (cytochrome P450) obey Michaelis-Menten kinetics:
v = [Vmax- s]/[Km + s] (2.25)
where v is the rate of the reaction, Vmax the maximum rate, Km the affinity constant (concentration at 50 % Vmax) and s the substrate concentration. Substrate concentration (s) is equal to or has a direct relationship to Cp^. In many cases Cpf (or s) are below the Km value of the enzyme system. However, in some cases (particularly the higher affinity P450s such as CYP2D6, see Chapter 7), Cpf (or s) can exceed the Km and the rate of metabolism therefore approaches the maximum (Vmax). As such the kinetics move from first order to zero order and the elimination of the drug is capacity limited. The term saturation kinetics is applied. Under these conditions
Cliu= Vmax/s (2.26)
and clearance depends on drug concentration.
These values are obtained from in vitro enzyme experiments. From the previous relationship between in vitro pharmacology measurements and free drug concentrations and those outlined here, it is reasonable to assume that clinical dose size can be calculated from simple in vitro measurements.
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