12 - substrates plasma concentration

The co-administration of drugs which induce the metabolic enzymes in the liver or small intestine can reduce the plasma concentrations of drugs which are substrates of the enzyme, leading to reduced drug effects. For example, the plasma concentrations of many drugs which are substrates of the enzyme CYP3A4, such as cyclosporine, are decreased by coadministration of rifampicin, which is an inducer of CYP3A4. 

The co-administration of drugs which inhibit the transporters involved in renal tubular secretion can reduce the urinaty excretion of drugs which are substrates of the transporter, leading to elevated plasma concentrations of the drugs. For example, probenecid increases the plasma concentration and the duration of effect of penicillin by inhibiting its renal tubular secretion. It also elevates the plasma concentration of methotrexate by the same mechanism, provoking its toxic effects. 

Irrespective of whether or not DA can cross the blood-brain barrier it will certainly be destroyed after oral administration by MAO and COMT in the gut and liver before achieving an adequate plasma concentration. Levodopa, by contrast, is not a good substrate for MAO, although metabolised by COMT (Fig. 15.4) and is transported across the gut and blood-brain barrier. 

The significance of P-gp, however, in affecting absorption and bioavailability of P-gp substrate drugs can be seen in studies in knockout mice that do not have intestinal P-gp. The gene responsible for producing that protein has been knocked out of the genetic repertoire. Those animals evidenced a sixfold increase in plasma concentrations (and AUC, area under the plasma concentration-time curve) of the anticancer drug paclitaxel (Taxol) compared to the control animals [54]. Another line of evidence is the recent report... 

A recent report on a NR2B selective NMDA receptor antagonist (9) supports the findings of Kalvass and Maurer [56], Rapid equilibration between plasma and CNS coupled with the lack of Pgp substrate activity led the authors to assume that plasma-free and brain-free drug concentrations were equivalent. An ex vivo receptor binding assay showed 50% occupancy at a total plasma concentration of 230 nM. Given a rat-free fraction of 15.3%, the authors concluded that 50% brain occupancy occurred at 35 nM unbound brain concentration, which was in reasonable agreement with the measured Ki of 3.4 nM versus the human receptor. 

Activators and inhibitors regulate not the amount of enzyme protein but the activity ( efficiency ) of that which is present. Two principal mechanisms of control are (i) competitive and (ii) allosteric. Competitive control (inhibition) occurs when a compound which is structurally similar to the true substrate binds to the active site of the enzyme. This is how a number of drugs and poisons bring about their effect. For example, a group of therapeutic drugs called statins are used to treat heart disease because by inhibiting a key enzyme called HMGCoA reductase, they reduce the hepatic synthesis of cholesterol and therefore the plasma concentration of that lipid. 

The apparent retinal influx clearance,. Kin,retina expressed as mL/(min g retina), of the test substrate labeled with either [3 H] or [14C] from the circulating blood to the retina is determined by integration plot analysis. In brief, rats are anesthetized, followed by injection of the test substrate (e.g., an [3H]-labeled compound, about 10 /u.Ci/head) into the femoral vein. After collection of plasma samples, rats are decapitated and the retinas removed. The retinas are dissolved in 2 N NaOH and subsequently neutralized with 2 N HC1. The radioactivity of retinal cell lysates is measured by liquid scintillation spectrometry. As an index of the retinal distribution characteristics of the radiolabeled test substrate, the apparent retina-to-plasma concentration ratio (Vd) as a function of time is used. This ratio [Vd(Q] (mL/g retina) is defined as the amount of [3H] per gram retina divided by that per milliliter plasma, calculated over the time-period of the experiment. The Kjn,retina can be described by the following relationship ... 

P450 system Efavirenz induces CYP3A4 in vitro. Compounds that are substrates of CYP3A4 may have decreased plasma concentrations when coadministered with efavirenz. Drugs that induce CYP3A4 activity would be expected to increase the clearance of efavirenz, resulting in lowered plasma concentrations. 

A rather new development is the orally available renin inhibitor aliskiren. It was approved by the U.S. Food and Drug Administration in 2007 for the treatment of hypertension. As mentioned above renin is a protease released on various stimuli from the jux-taglomerula apparatus in the kidney. Its release is the limiting step in the whole renin-angiotensin cascade. Since renin is highly substrate-specific its inhibition can be expected to have very little unspecific side effects. The result of an effective blockade of this enzyme is a reduced angiotensin I and angiotensin II formation. In contrast to ACE-inhibition or ATi-receptor blockade, the plasma concentrations of both peptides stay low. No interaction with other systems like the Kallikrenin-Bradykinin system seems to take place. 

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