Absorption, distribution, metabolism and elimination

Gastric pH is higher in newborns (pH 6-8) than in adults (pH 1-3), thus causing differences in ionization and absorption of certain chemicals (Radde, 1985). Adult levels of gastric acid production are reached at about two years of age. The alkaline gastric pH in newborns and infants may lead to enhanced bioavailability of weakly basic compounds but reduced bioavailability of weakly acidic compounds (Alcorn McNamara, 2003). 

The difference in volume of distribution between adults and children may not always lead to corresponding differences in blood or tissue concentrations. This is particularly likely to be the case during continuous exposures to chemicals that lead to a steady-state 

Metabolism and elimination rates are generally lower in neonates than in adults. The elimination half-lives of substances used as indicators of liver function (e.g. bromosulfthalein, bilirubin), for example, are longer in newborns than in adults. Renal clearance has been shown to be lower in neonates than in older children and adults, for all chemical classes lipophilic, hydrophilic, and organic ions (Clewell et al., 2002). Glomerular filtration rate at normal-term birth is about one third of the adult value when expressed on the basis of body surface area and matures in about six months. On the other hand, the tubular reabsorption process reaches adult levels within a few days after birth. 

A systematic comparison of the available information on age-dependent maturation of metabolic and elimination processes as well as the toxicokinetics of chemicals in developing neonatal and young animals with that in infants and children can be found elsewhere (Gladtke, 1973 Stewart Hampton, 1987 Crom, 1994 Renwick, 1998 Clewell et al., 2002 Alcorn McNamara, 2003 Kearns et al., 2003 de Zwart et al., 2004 Ginsberg et al., 2004c). Table 2 summarizes the age dependency of toxicokinetic processes and determinants in children compared with adults. 

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During the past decade, numerous articles reviewing the effects of aging on pharmacokinetic processes (i.e., absorption, distribution, metabolism, and elimination) have been published [115 124h]. An outline of the observations made in these reports is supplied in Table 5. The absorption process is the only process that will be covered in depth in this chapter, as this is the process that can most easily be manipulated through formulation techniques. 

Toxicokinetic—The study of the absorption, distribution, metabolism, and elimination of toxic compounds in the living organism. 

The development of combinatorial chemistry and high throughput screening programmes has stimulated efforts to find experimental and computational models to estimate and predict drug absorption, distribution, metabolism and elimination based on drug physicochemical properties. 

The nature of toxic damage produced by a chemical, the part of the body where that damage occurs, the severity of the damage, and the likelihood that the damage can be reversed, all depend upon the processes of absorption, distribution, metabolism and elimination, ADME for short. 

Bullock P, Larsen D, Press R, Wehrman T, Martin DE. (2008) The absorption, distribution, metabolism and elimination of bevirimat in rats. Biopharm Drug Dispos 29 396-405. 

As with classic compartment pharmacokinetic models, PBPK models can be used to simulate drug plasma concentration versus time profiles. However, PBPK models differ from classic PK models in that they include separate compartments for tissues involved in absorption, distribution, metabolism and elimination connected by physiologically based descriptions of blood flow (Figure 10.1). 

Propiopromazine has been used in all the domesticated animals. Although very limited information is available on the absorption, distribution, metabolism, and elimination of propiopromazine in animals, several studies (103) have reported the presence of propiopromazine in pig kidney collected from abattoirs, so that human exposure should therefore be presumed. Both pigs and horses are able to metabolize propiopromazine, at least in part. The drug binds extensively to tissue proteins, and also accumulates in fatty tissues. 

Pharmacokinetics (PK) is the science that describes the time course of a circulating drug concentration in the body resulting from administration of a certain drug dose. In comparison, pharmacodynamics (PD) is the science that describes the relationship of the time course of drug concentration and the drug effects in the body (Meibohm and Derendorf, 1997). Key determinants of the PK of a drug include absorption, distribution, metabolism, and elimination (ADME) (Lin et al., 2003), as discussed in Chapter 1. 

V. In vivo pharmacology pharmacokinetics pharmacology screening Animal Determine pharmacokinetic profile of ohgos, i.e., absorption, distribution, metabolism, and elimination Determine pharmacological effects of ohgos on host tissues other than desired effects... 

Nicklin, P.L., S.J. Craig, and J.A. Phillips. 1998. Pharmacokinetic properties of phos-phorothioates in animals - absorption, distribution, metabolism and elimination. In Crooke, S.T. (Ed.), Antisense Research and Applications. Springer-Verlag, Berlin, pp. 141-168. 

The pharmacokinetic phase of drug action includes the Absorption, Distribution, Metabolism and Elimination (ADME) of the drug. Many of the factors that influence drug action apply to all aspects of the pharmacokinetic phase. Solubility (see Section 3.3), for example, is an important factor in the absorption, distribution and elimination of a drug. Furthermore, the rate of drug dissolution, that is, the rate at which a solid drug dissolves in the aqueous medium, controls its activity when a solid drug is administered by enteral routes (see Section 2.6) as a solid or suspension. 

A Abe ACE ACh ADME ADR Ala Arg Asp ATP dATP AUC Adenine Abequose Angiotensin-converting enzyme Acetyl choline Absorption, distribution, metabolism and elimination Adverse drug reaction Alanine Arginine Aspartate Deoxyadenosine triphosphate Adenosine triphosphate Area under the curve... 

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