Orally administered drugs clearance

On the other hand, for any drug that is degraded at a point between the postabsorption site and entry into the systemic circulation, the systemic availability— bioavailability— will be less than the absorption. An orally administered drug that undergoes extensive first-pass hepatic clearance may give rise to poor oral bioavailability despite being efficiently absorbed from the gastrointestinal (GI) tract into the splanchnic circulation. 

Limited pharmacokinetic data are available for this compound. Orally administered drug has a half-life of about I. hours and a total body clearance of 4.4 mL/min perkg.lh mean peak plasma concentrations are reported to van... 

In the section on noninformative priors, a precision of 0.0001 corresponds to a variance of 10,000 (SD = 100), and if it were assumed that the underlying parameter distribution were lognormal (which is common in PK/PD problems), then the 95% interval of the priors would be essentially 0 and -foo. a possible example of a biologically plausible but still low-information prior follows. In this example the values of the parameters are chosen arbtitrarily and any mean values can be used that suit the likely situation. Any choice of mean values will require slight adjustment of the precision matrix however, this is quite straightforward. For a typical orally administered drug with an assumed fraction absorbed of 1, and mean population parameters for clearance, volume, and absorption rate constant that are the natural log of 1 (L/h), 40 (L), and 1 (h ), respectively (just over a 24 hour half-life), then the prior could be... 

These results indicate that, in addition to effectiveness by inhalation and parenteral administration, SNA is well absorbed in man when administered orally. The drug is 60-70% bound to plasma proteins, the volume of distribution is high (approximately 500 L In an 80-kg man), clearance is largely a result of metabolic processes, the half-life Is quite variable from one person to another, and the drug and its metabolites are excreted principally in the urine, regardless of whether it is given orally or intravenously. 

On the other hand, the volume of disfiibution is significantly increased for orally administered trimethoprim in feverish rabbits compared with their healthy counterparts and absorption is reduced (38). The significance of these changes can be appreciated if one considers that the total body clearance of a drug is... 

All orally administered chugs must pass through the gastrointestinal tract to reach the blood and thus pass the barrier formed by the enterocytes in the intestine. For years, low first-pass bioavailability of a drug was attributed mainly to clearance via hepatic metabolism and biliary clearance or incomplete absorption in the intestine due to poor solubility or intrinsic permeability properties. Although these are important factors in determining the overall oral bioavailability of certain... 

The intrinsic kinetic properties of the victim drug also influence the potential clinical consequences of an interaction. For orally administered medications that undergo significant presystemic extraction, impairment of clearance by a CYP inhibitor may produce increases in bioavailability (reduced presystemic extraction) as a consequence of reduced clearance. The effects may be particularly dramatic for CYP3A substrates (such as triazolam, midazolam, or buspirone) that undergo both hepatic and enteric presystemic extraction. As an example, coadministration of the CYP3A inhibitor ketoconazole with triazolam produced very large increases in area under the plasma concentration-time curve... 

While numerous studies have evaluated the effect of oral contraceptives and postmenopausal hormone replacement on drug clearance, many were flawed by poor study design. Table 21.1 lists studies that were of crossover or sequential design such that each subject was evaluated in the contraceptive phase and placebo phase. These study designs minimize the effect of interindividual variability. In most studies there was no effect of hormonal therapy on drug metabolism, but in some there were interactions that inhibited or increased the metabolism of concurrently administered drugs. 

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