MOLECULAR PROPERTIES RELEVANT FOR ADME PROFILING in .NET

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MOLECULAR PROPERTIES RELEVANT FOR ADME PROFILING
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Biopharmaceutical pro ling assays are used to predict the behavior of drug candidates against the number of hurdles a compound needs to overcome to become a drug, like absorption, distribution, metabolism, and elimination. The main absorption pathways in the GIT epithelium are shown in Figure 15.1, while Table 15.1 lists the parameters used to address the different aspects of drug disposition. As oral delivery has become a must due to patient compliance and marketing reasons, parameters governing GIT absorption are usually of primary interest. Solubility and permeability are the two main physicochemical parameters relevant for oral absorption. Compounds can be classi ed in four categories according to the BCS classi cation scheme (Table 15.2) proposed by Gordon Amidon.1 The technologies currently used to access physicochemical parameters of interest in ADME pro ling are listed in Table 15.3.
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molecular properties relevant for adme pro ling
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Lumen 1 2 3 4 5
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Unstirred layers
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Figure 15.1. Absorption pathways. The rst common step for all pathways in GIT absorption is the diffusion throught the unstirred layers. (1) Transcellular (most common pathway for drugs), (2) paracellular (small, water soluble compounds), (3) facilitated transport, (4) active tranport (saturable, requires ATP), and (5) ef ux pumps (i.e., pGp. MRP).
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Table 15.1. Biophamaceutical Classi cation Scheme1 High Solubility High permeability Class I Dissolution rate limits absorption Carbamazepine Ketoprofen Propranolol Class III Permeability limits absorption Famotidine Nadolol Valsartan Low Solubility Class II Solubility limits absorption Chlorpromazine Diclofenac Nortriptyline Class IV Signi cant problems for oral delivery expected Ciclosporine Furosemide Terfenadine
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Low permeability
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potential and limitations
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Table 15.2. Parameters Used to Address Biopharmaceutical Properties In uencing Drug Disposition
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Biopharmaceutical Property Oral absorption
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Parameter Solubility Permeability Ionization constant (pKa) Permability Ef ux (pGp) Active transports Lipophylicity Lipophilicity (log P) Molecular size Metaboic stability in liver microsomes Chemical stability P450 inhibition
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Blood brain penetration
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Distribution excretion Stability Drug drug interaction (safety)
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Table 15.3. Methods to Measure Parameters of Interest in Drug Disposition Prediction Property Partition/distribution coef cients (log P and D) Method RP-HPLC log k Shake- ask/HPLC Dual-phase potentiometric titration Octanol coated columns Liquid arti cial membranes Caco-2 monolayers MCDK monolayers PAMPA Hexadecane liquid membrane HPLC-IAM log k Potentiometric titration Spectrophotometric titration Fast-gradient spectrophotometric titration Capillary electrophoresis Nephelometric titration Turbidimetry Dissolution template titration Shake- ask/HPLC Flow cytometry titration UV shake-plate
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Permeability
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Ionization constants
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Solubility
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Note: High-throughput methods are indicated in bold.
solubility determinations
15.3. SOLUBILITY DETERMINATIONS
Solubility plays an essential role in drug disposition as passive drug transport across a biological membrane is the combined product of both permeability and solubility (Fick s rst law). Poor solubility has been identi ed as the cause of numerous drug development failures.2 It is one of the components of the BCS1 and, if not properly taken into account, leads to erroneous results in a number of assays3 (i.e., Caco-2 as well as arti cial model membrane permeability, binding af nity determinations). In the ADME eld, solubility is particularly important for immediate release BCS class II drugs, for which absorption is limited by solubility (thermodynamic barrier) or dissolution rate (kinetic barrier).1,4Although it may appear relatively simple at rst glance, the experimental determination of solubility is often dif cult due to the complexity of the solution chemistry involved. A number of factors like supersaturation, dissolution rate, aggregation reactions, micelle formation, effect of ions and buffers, presence of impurities, and ionic strength come into play, and if not properly taken into account, they lead to erroneous results. The measurement of aqueous solubility can be divided into ve components5
Temperature control Puri cation of solute and water Equilibration kinetics Separation of phases Analysis of the saturated solution
The dif culty to get reliable results usually increases as solubility decreases. Incorrect solubility values can result from improper execution of any of the steps above. 15.3.1. Equilibration Kinetics
Since dissolution is a time-dependent process, the contact between the powder and water is important. The kinetics depends on the dissolution rate, which is itself in uenced by the type of agitation and the surface of contact between the solute and water (dictated by particle size). Dissolution kinetics is usually inversely correlated with solubility, although there is considerable variation in this relationship. The approach to equilibrium is usually asymptotic, which means that the solute initially enters in solution quite rapidly, and as it approaches equilibrium, the rate of dissolution decreases. To check that the equilibrium has been reached, one must take samples at various time points up to a constant concentration is obtained.