Absorption (Pharmacokinetics) Related terms: Pharmacokinetics: Absorption is variable and dependent upon many factors Pharmacodynamics, including integrity of skin, dose, vehicle used, and use of occlusive dressings. Combination Therapy, Drug Therapy, Metabolism, From: Drugs for the Geriatric Patient, 2007 Euion Sug food Urine, Affect, Toxicity View full index > ADME-Tox Approaches H. Lennernas, B. Abrahamsson, in Comprehensive Medicinal Chemistry ||, 2007 5.42.3.2 Biopharmaceutics Classification System in Drug Discovery and Preclinical Development Pharmacokinetic (absorption, distribution, metabolism, and excretion — ADME) parameters are today considered to have ‘ crucial role in the selection process of oral candidate drugs for product development.” This understanding has also most probably contributed to significantly reduce the number of developmental failure due to pharmacokinetic factors during recent years." Fundamental BCS parameters, such as permeability, solubility, and fraction dose absorbed, are among those ADME parameters and therefore ithas been suggested that these fundamental BCS parameters should be useful in both the discovery and early development process.1,3? For instance, itis clear that new compounds with a very low permeability andor solubility/dissolution will certainly result in low and highly variable bioavailability, which may limit the possibilities that a clinically useful product can be developed. It is obvious that 2 selection of candidates that fulfil the BCS requirement of high permeability/high solubility (class |) almost guarantees the absence of failures due to incomplete and highly variable Gl absorption. However, these BCS limits are generally too conservative to use as acceptance criteria in drug screening since many useful drugs can be found in classes II-IIl and even class 1V.2° First ofall, a class | drug is expected to provide complete absorption whereas a certain reduction in bioavailability due to permeability or solubility, as well as due to other reasons (e.g, first-pass metabolism), is generally acceptable. A summary of the different factors that have to be taken into account when defining more relevant acceptance criteria follows: 1. Acceptability of a low and highly variable bioavailability depending on © medical need (© width of therapeutic window © potency (© substance manufacturing costs. 2. Potential for poor in vivo predictability of early permeability and solubility characterizations, due to, e.g., © active transport across the gut wall © high paracellular transport through gut wall © in vivo solubilization by bile salt micelles. 3. Opportunity to use formulation approaches that improve bioavailability, e.g.© dissolution and solubility enhancement © permeation enhancers. Thus, BCS points out some important variables in the screening of drug candidates whereas the proposed limits are less Useful as acceptance criteria in a drug discovery contest. Experimental methods and relevant acceptance criteria regarding permeability and solubility are needed in the early drug discovery process. **° Such procedures have also been introduced in the industry, including solubility screens using turbidimetric measurements and automatic permeability screens in cell-based systems (such as Caco-2 cell model). There appears to be a good correlation between in vitro and in vivo permeability for drugs with passive diffusion as the main transport mechanism, but there is a significant deviation for drugs absorbed through transporters.2* It is also considered that the interpretation of the importance of efflux carrier on intestinal absorption process is overrated based on results obtained in tissue cell cultures (e.g., Caco-2 cells).4°,2,*°,"! For instance, based on only cell culture data (Caco-2 cells), it was shown that the in vitro permeability of fexofenadine in the absorptive direction increased by approximately 200-300% in the presence of various P-gp inhibitors (such as verapamil, ketoconazole, and GF 120918) and that low passive diffusion was the main reason for the incomplete and variable intestinal absorption. Interestingly, an in vivo perfusion of the proximal part of jejunum with our Loc-I-Gut technique showed that the in vivo permeability was affected by neither ketoconazole nor verapamil at clinical doses (Figure 3).”,*? It clearly shows that the cell monolayer is too poorly defined to quantitatively predict drug-drug interactions at the transporter level. These cell models can only provide quantitative in vivo predictions of drug transport if an extensive mapping oftthe expression of functional activity of these membrane transporters is done. Therefore, there is a need to develop in vitro techniques with functional expressed transporter activities that are better correlated to the various regions of the human intestinal tract.36°°4143-44 These in vitro permeability data need to be accurately compared with the corresponding in vivo data, We have over the past 15 years determined the human in vivo jejunal permeability with a single-pass perfusion technique (Figure 3) fora number of structurally different drugs, as illustrated in Figure 5. In addition, a critical interpretation and extrapolation of the in vivo relevance data of intestinal transport are crucial for a meaningful use of these improved cell monolayers. It is well known that the intestinal absorption potential of drugs that are mainly transported by passive diffusion maybe be predicted from molecular properties, such as polar surface area, hydrogen bonding, log P, log D, and molecular weight. Accordingly, the fundamental BCS parameters are suggested to be based on theoretical descriptors in the future and computational approaches have also been developed for permeability and solubility determinations.!10 324 “® iffurther refinement can be achieved for such methods, such as quantitative structure-activty relationship (QSAR) models to optimize ADME properties, it may be possible in the future to displace cell-based permeability screens and solubility estimates in screening for new drug molecules.*3,3¢ However, simple physicochemical descriptors of solubility and permeability must probably be assembled into and validated in more physiologically based models to be able to accurately predict human intestinal absorption.*°-*? Recently Lindahl et al. demonstrated that in vitro permeability values could be used to simulate the absorption from various intestinal segments in humans.®¥ An intermediate approach for permeability determinations, between physicochemical and physiologically based methods, is the use of artificial membranes.*,5> Such techniques provide a pure estimate of transcellular permeability without influence from transporters or the unstirred water layer present in cell-based models, which could provide useful feedback to chemists in the screening phase. Finally, itis important to understand that even if absorption properties are acceptable the drug may have a limited clinical use due to an extensive first-pass extraction in the gut and/or liver that is outside the topic of the present chapter. In drug discovery there is a strong demand for early information on drug properties such as ADME variables. Several in vitro ADME screens have significantly increased the amount of experimental data generated in the early drug discovery process. In addition to these experimental techniques, there is a need for different in silico methods that can predict ADME variables with fairly high accuracy. For instance, ADME filters that can sort out drugs with undesirable ADME properties can be applied in virtual screening or drug design so as to reduce compound attrition rates. The basis for constructing these predictive models is the existence of hish-auality exoerimental data. Several data sets exist in theliterature and have been used for building models that predict ADME-related variables such as Per fa, and solubility4*50 Unfortunately, many of these data sets have been compiled from different sources and not with the ‘same experimental conditions, making a direct validation of the different models difficult. Another shortcoming with the existing data sets is that different sets of drugs have been used for modeling different properties. This makes it difficult to construct robust and more complex quantitative models, of for example, drug absorption that would be based on log Plog D, solubility, intestinal permeability, metabolic stability, and carrier-mediated membrane transport data. In this case @ relevant and common data set is essential that represents the available ADME space. New experimental tools are also constantly being developed that aim to complement in vitro and/or in vivo experiments. Many data sets in the literature contain high-quality experimental ADME-related data. Unfortunately, many of these include compounds that, are not commercially available. Others are not structurally diverse, which is an important property when attempting to build predictive models of ADME properties. In the later phases of preclinical development, various animal models are often used to evaluate the absorption potential of new drugs. The predictive value for humans of various models can be guided by BCS. For example, the rat is considered an appropriate mode! that predicts permeability-limited human intestinal absorption well. In contrast, another very common model, the dog, has been shown to provide faster intestinal permeability and increased absorption compared to humans of low-permeability drugs whereas high-permeability drugs seem to be rapidly and completely absorbed in dog similarly to human. ®,* In case of solubility limitations of drug absorption, the similarity in basic Gl physiological conditions will be the primary determinant for the usefulness of an animal model. The key aspects are GI volumes, pH, and presence of solubilizing agents like bile acids. Several comparisons of these properties have been published for dog, rat, and human as well as other animal models.“*-*7 Generally, the dog has been proposed to a reasonable model for BCS class II drugs due to the similarities in relevant aspects of GI physiology. Fairly similar drug, solubility has also been shown (Figure 6) for a number of drugs in human and dog intestinal fluid obtained both under fasting and fed conditions in a recent study. * Thus, usefulness of animal models in drug absorption studies is dependent on the BCS characteristics of the drug compound. Personalizing Medicine ‘Anika Niambi Al-Shura BSc., MSOM, Ph.D, in Integrative Cardiovascular Chinese Medicine, 2014 3 Clinical Uses for Drugs According to Pharmacogenomics Genetic variants can affect drug pharmacokinetics (absorption, distribution, metabolism, and excretion) and/or the drug pharmacodynamics (interaction and its mechanism). (2) Warfarin: + Cytochrome P450 + Genotype (CYP2C9) + crpar2 + Vitamin K epoxide reductase complex genotype 1 (VKORCI) + RS06Qand 202106 These genes can affect bleeding, hyper-coagulation and metabolism within the liver. In addition, vitamin K levels affect drug responses. ©) Clopidogrel: + Cytochrome P450 + Metabolizing liver enzyme: CYP2C19 + Paraoxonase I (PON!)