Metabolism, Pharmacokinetics, Bioavailability

As mentioned above, bioavailability is the degree to which a drug reaches the intended site of action. The amount of drug that reaches systemic circulation will depend on the processes of absorption, distribution, and biotransformation (when the route of administration exposes the drug to first-pass metabolism). Pharmacokinetics are often linear and when they are nonlinear it is often due to a saturation of protein binding, metabolism, or active renal transport. 

Pharmacokinetics Bioavailability of tablet vs liquid is approximately 90%. Diphenoxylate is rapidly, extensively metabolized to diphenoxylic acid (difenoxine), the active major metabolite. Elimination half-life is approximately 12 to 14 hours. An average of 14% of drug and metabolites are excreted over 4 days in urine, 49% in feces. Urinary excretion of unmetabolized drug is less than 1% difenoxine plus its glucuronide conjugate constitutes approximately 6%. 

Pharmacokinetics All oral PPIs are rapidly absorbed and undergo hepatic metabolism. The bioavailability of the oral PPIs ranges from 30% to 85%. All of the PPIs have a short elimination PA (< 2 hr), but this has minimal effect on the duration of antisecretory action due to irreversible binding to the proton pump. Both cisapride and metoclopramide have a rapid onset of action, < 1 hr. Both agents have a similar oral bioavailability 50%-80% and are extensively metabolized by the liver to inactive metabolites. 

Shah V P, Midha K K, Dighe S, et al. (1991). Analytical methods validation Bioavailability, bioequivalence and pharmacokinetics studies. Conference Report. Eur. J. Drug Metabol. Pharmacokinet. 16 249-255. 

Metabolism, pharmacokinetics, and bioavailability studies, initially on a preclinical level but later after human testing is approved, are also supported by LC analytical methods of drug and metabolite levels determination in various biological fluids and tissues. These studies and those to support further toxicology testing are the subject of other articles. 

Lack of favorable ADME properties (absorption, distribution, metabolism, elimination) can preclude therapeutic use of an otherwise active molecule. The clinical pharmacokinetic parameters of clearance, half-life, volume of distribution, and bioavailability can be used to characterize ADME properties. 

Little is known regarding the pharmacokinetic properties of volatile nitrites in humans, particularly isobutyl nitrite and its primary metabolite, isobutyl alcohol. In rodents, after an intravenous infusion of isobutyl nitrite, blood concentrations peaked rapidly and then declined, with a half-life of 1.4 minutes and blood clearance rate of 2.9 L/min/kg (Kielbasa and Fung 2000). Approximately 98% of isobutyl nitrite is metabolized rapidly to isobutyl alcohol, concentrations of which also decline rapidly, with a half-life of 5.3 minutes. Bioavailability of inhaled isobutyl nitrite at a concentration of 300-900 ppm is estimated to be 43%. 

Toluene, volatile nitrites, and anesthetics, like other substances of abuse such as cocaine, nicotine, and heroin, are characterized by rapid absorption, rapid entry into the brain, high bioavailability, a short half-life, and a rapid rate of metabolism and clearance (Gerasimov et al. 2002 Pontieri et al. 1996, 1998). Because these pharmacokinetic parameters are associated with the ability of addictive substances to induce positive reinforcing effects, it appears that the pharmacokinetic features of inhalants contribute to their high abuse liability among susceptible individuals. 

The pharmacokinetic profile of (16) and its two analogues were investigated in Sprague-Dawley rats. Removal of the metabolically labile tert-butyl group on the aryl moiety slowed metabolism and the rate of clearance. However, the overall half-life of (17a) was unaffected because of a lower volume of distribution. On the other hand, (17b) showed an increased half-life (ca. 3h versus 1 h) compared to (16) and (17a). While the oral bioavailability of (16) was negligible, (17a) and (17b) were better absorbed, with bioavailability values of 39% and 17%, respectively. While undoubtedly improved in terms of pharmacokinetics compared to (16), the bioactivity of (17a) and (17b) awaits validation in vivo. 

There are several pharmacokinetic differences between loop diuretics. Fifty to sixty percent of a dose of furosemide is excreted unchanged by the kidney with the remainder undergoing glucuronide conjugation in the kidney.17 In contrast, liver metabolism accounts for 50% and 80% of the elimination of bumetanide and torsemide, respectively.17 Thus, patients with ARF may have a prolonged half-life of furosemide. The bioavailability of both torsemide and bumetanide is higher than for furosemide. The intravenous (IV) oral ratio for bumetanide and torsemide is 1 1, bioavailability of oral furosemide is approximately 50%, with a reported range of 10% to 100%.18... 

The third step is to optimize the lead molecule through iterative chemical synthesis and biological testing, aiming to obtain molecules with the required potency (typically nanomolar), selectivity, bioavailability, and DMPK (drug metabolism and pharmacokinetics) properties. This step usually requires considerable time and resources usually the synthesis of hundreds of compounds is needed to deduce a robust SAR (structure-activity relationship). Such resources can be considerably reduced and the... 

Dopamine, a vasodilator, has been widely used for treatment of acute circulatory failure. However, since dopamine is rapidly metabolized when administered orally, its use has been limited to intravenous infusion. Murata et al., studied the bioavailability and the pharmacokinetics of orally administered dopamine (DA). The oral administration of DA to dogs resulted in an absolute bioavailability of approximately 3%. To minimize the extensive first-pass metabolism of DA, a dopamine prodrug, V-(/V-acetyl-l-mcLhionyl)-o,o-bis(cLhoxycarbonyl)dopamine (TA-870), was synthesized [28] (Fig. 6). Since DA is a substrate for both mono-... 

This chapter will review some of the important methods for carrying out in vivo absorption and bioavailability studies, as well as attempt to provide an overview of how the information may be used in the drug discovery process. The chapter is aimed at medicinal chemists and thus will focus on the use of animals in discovery phase absorption, distribution, metabolism, and excretion/pharmacokinetic (ADME/PK) studies, rather than the design of studies that are for regulatory submission, or part of a development safety package. 

Pharmacokinetic Definition of Intestinal Absorption (fa), Presystemic Metabolism (Ec and Eh) and Absolute Bioavailability (F) of Drugs Administered Orally to Humans... 

The most useful pharmacokinetic variable for describing the quantitative aspects of all processes influencing the absorption (fa) and first-pass metabolism and excretion (Eg and Eh) in the gut and liver is the absolute bioavailability (F) [40]. This pharmacokinetic parameter is used to illustrate the fraction of the dose that reaches the systemic circulation, and relate it to pharmacological and safety effects for oral pharmaceutical products in various clinical situations. The bioavailability is dependent on three major factors the fraction dose absorbed (fa) and the first-pass extraction of the drug in the gut wall (EG) and/or the liver (EH) (Eq. (1)) [2-4, 15, 35] ... 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

Obach et al. [27] proposed a model to predict human bioavailability from a retrospective study of in vitro metabolism and in vivo animal pharmacokinetic (PK) data. While their model yielded acceptable predictions (within a factor of 2) for an expansive group of compounds, it relied extensively on in vivo animal PK data for interspecies scaling in order to estimate human PK parameters. Animal data are more time-consuming and costly to obtain than are permeability and metabolic clearance data hence, this approach may be limited to the later stages of discovery support when the numbers of compounds being evaluated are fewer. 

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