Peripheral bioavailabilities

In addition, several peripheral bioavailability terms can be calculated to describe the extent to which the drug is distributed out of the sampling compartment. 

AUC peripheral bioavailability is the ratio of the amount of drug at steady state in the peripheral system to the amount in the sampling compartment this is also referred to as the residence time partition coefficient... 

The descriptive pharmacokinetic terms illustrated above only begin to touch the surface of the analysis that can be done. When the rate of change of the response function is evaluated, the derivative of C(t), then other clearance terms, peripheral bioavailabilities, and mean time parameters can be computed. These will be examined in Chapter 16 describing linear systems analysis. In addition, it is possible to use intravenous results and extravascular results to deconvolve the input function from the characteristic response function to assess various mean time parameters that examine the arrival of the drug into the sampling compartment. 

The dopamine precursor l-DOPA (levodopa) is commonly used in TH treatment of the symptoms of PD. l-DOPA can be absorbed in the intestinal tract and transported across the blood-brain barrier by the large neutral amino acid (LNAA) transport system, where it taken up by dopaminergic neurons and converted into dopamine by the activity of TH. In PD treatment, peripheral AADC can be blocked by carbidopa or benserazide to increase the amount of l-DOPA reaching the brain. Selective MAO B inhibitors like deprenyl (selegiline) have also been effectively used with l-DOPA therapy to reduce the metabolism of dopamine. Recently, potent and selective nitrocatechol-type COMT inhibitors such as entacapone and tolcapone have been shown to be clinically effective in improving the bioavailability of l-DOPA and potentiating its effectiveness in the treatment of PD. 

L-dopa is effective in the treatment of Parkinson s disease, a disorder characterised by low levels of dopamine, since L-dopa is metabolised into dopamine. However, this biosynthesis normally occurs in both the peripheral nervous system (PNS) and the central nervous system CNS. The related drug carbidopa inhibits aromatic L-amino acid decarboxylase only in the periphery, since it does not cross the blood-brain barrier. So, when carbidopa is given with L-dopa, it reduces the biosynthesis of L-dopa to dopamine in the periphery and, thus, increases the bioavailability of L-dopa for the dopaminergic neurons in the brain. Hence, carbidopa increases the clinical efficacy of L-dopa for Parkinsonian patients. 

Antitrypsin (sheep) 52 kDa Aerosol (nebulized) Solution 50 % in 50 h lost from peripheral lung bioavailability. 16 % via lymphatics... 

Consequently, bioavailability depends on the route of administration as well as the drug s ability to cross membrane barriers. Once in the systemic circulation, further distribution into peripheral tissues may also be important in allowing the drug to reach the target site. Many drugs must eventually leave the systemic capillaries and enter other cells. Thus, drugs have to move across cell membranes and tissue barriers to get into the body and be distributed within the body. In this section, the ability of these membranes to affect absorption and distribution of drugs is discussed. 

While many aspects of nonlinear pharmacokinetic behavior may impact on the above equation, the more relevant pharmacokinetic processes for ASOs are absorption and distribution at or below therapeutic or nontoxic plasma concentrations. Nonlinear absorption or distribution processes can affect AUC terms in a nonproportional manner when different doses are compared, thereby resulting in an inaccurate determination of bioavailability. This has been shown to occur on numerous occasions for compounds such as ascorbic acid or naproxen [59-62]. Such cases require an understanding of the capacity-limiting cause of the nonlinearity and the pharmacokinetic processes upon which this impacts, in case of ASOs absorption and intercompartmental distribution processes from the central compartment into the peripheral tissues. With this understanding, various methods may then be applied to best approximate the rate of change of the plasma concentrations from one sampling time to the next allowing for an estimate of the absolute BAV. 

In clinical practice, L-dopa is conventionally administered in combination with a peripherally acting inhibitor of aromatic L-amino acid decarboxylase (e.g., carbidopa). If L-dopa is administered alone, the drug is largely decarboxylated by enzymes in the intestinal mucosa and other peripheral sites. Inhibition of peripheral decarboxylase by carbidopa markedly increases the fraction of orally administered L-dopa that remains unmetabolized and available to enter the brain (i.e., its bioavailability). 

Isradipine (Fig. 7.5) is a further nifedipine analogue, which has been used in the treatment of hypertension either alone or in combination with diuretics. Isradipine possesses high calcium antagonist activity, which results in a peripheral vasodilatation without any detrimental effect on cardiac conduction. Its oral bioavailability is 90-95% of the administered dose, but the hepatic first-pass effect reduces this to 15-24%. Isradipine was shown to possess anti-atherosclerotic activity in a number of experimental models, but clinical studies (MIDAS) failed to confirm these findings in patients. 

Figure 2.10 Amphetamine 30, methamphetamine 31, and methylenedioxymethamphetamine 32 (MDMA, ecstasy, XTC) are lipophilic compounds with good oral bioavailability they easily cross the blood-brain barrier to exert central nervous system effects. Dopamine 33, norepinephrine (noradrenalin) 34, and epinephrine (adrenaline) 35 are polar phenethylamines they have poor oral efficacy and do not pass the blood-brain barrier, producing only peripheral effects after intravenous application. Ephedrine 36 has intermediate lipophilicity besides its peripheral effects it also acts as a central stimulant. Although L-dopa 37 is even more polar than dopamine 33, it is orally active and crosses the blood-brain barrier by active transport mediated by the amino acid transporter.

Cmjx. maximum plasma rormitratbn Qnjn, minimum plasma ronc ntration, F, bioavailability ti/2, elimination half-life NtRTIs Plasma NtRTl t,y intraoellular (peripheral blood mononuclear alls) NtRTI-triphosphate t,/2 plasma t,/2 only for other classes. Oose adjustment may be required for weight, renal, or hepatic disease and drug interactions. 

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