Drug elimination hepatic

The mass transfer coefficients may also be expressed in units of time-1 by multiplying by the appropriate compartmental volume term. Irreversible drug elimination from the tissue requires the addition of an expression to the differential equation that represents the subcompartment in which elimination occurs. For instance, hepatic drug elimination would be described by a linear or nonlinear expression added to the intracellular liver compartment mass balance equation since this compartment represents the hepatocytes. Formal elimination terms are given below for the simplified tissue models. 

Plasma level monitoring The majority of patients treated successfully had trough plasma levels between 0.2 and 1 mcg/mL. The probability of adverse experiences, especially cardiac, may increase with higher trough plasma levels, especially levels greater than 1 mcg/mL. Monitor trough plasma levels periodically, especially in patients with severe or moderate chronic renal failure or severe hepatic disease and CHF, as drug elimination may be slower. 

What makes prediction of drug elimination complex are the multiple possible pathways involved which explain why there is no simple in vitro clearance assay which predicts in vivo clearance. Because oxidative metabolism plays a major role in drug elimination, microsomal clearance assays are often used as a first line screen with the assumption that if clearance is high in this in vitro assay it is likely to be high in vivo. This assumption is often, but not always true because, for example, plasma protein binding can limit the rate of in vivo metabolism. However, compounds which have a low clearance in hepatic microsomes can be cleared in vivo via other mechanisms (phase II metabolism, plasmatic errzymes). Occasionally, elimination is limited by hepatic blood flow, and other processes like biliary excretion are then involved. The conclusion is that the value of in vitro assays needs to be established for each chemical series before it can be used for compound optimization. 

The pharmacokinetic term clearance (CT) best describes the efficiency of the elimination process. Clearance by an elimination organ (e.g., liver, kidney) is defined as the volume of blood, serum, or plasma that is totally cleared of drug per unit time. This term is additive the total body or systemic clearance of a drug is equal to the sum of the clearances by individual eliminating organs. Usually this is represented as the sum of renal and hepatic clearances CT = CT renal -I- CL hepatic. Clearance is constant and independent of serum concentration for drugs that are eliminated by first-order processes, and therefore may be considered proportionally constant between the rate of drug elimination and serum concentration. 

Propranolol is chemically a naphthol derivative (dl-(isopropylamino)-3-(l-naphthyloxy)-2-propanol). It is a racemic mixture, and the laevo form is the active P-adrenergic blocking agent [10]. After oral administration, it is completely absorbed [11]. However, the systemic availability is relatively low with considerable variation in plasma levels [12,13]. The hepatic extraction of propranolol is about 80- 90%, and thus the main route of drug elimination is via hepatic metabolism [14]. One of the maj or metabolites of propranolol is 4-hydroxypropranolol, and the half-life has been reported to be 3 l-l/2h [15-18]. Since the drug is rapidly metabolized after oral administration, it necessitates a multiple dosage after oral strict patient compliance. 

Abnormal drug elimination or metabolism occurs when a combination of drugs is used. Induction or inhibition of hepatic enzymes, as with an androgen... 

Oxybutynin has a relatively low oral bioavailability (6%) due to an extensive first-past presystemic metabolism after administration [194], Indeed, the absence of intact oxybutynin in urine suggests that the major elimination pathway of this drug is hepatic metabolism [195]. The compound is readily converted to its stable toxic metabolite, iV-desethyloxybutynin by cytochrome P450-mediated oxidation [196], Following oral administration of oxybutynin, peak plasma concentrations are reached within 1 h. The short half-life of this drug (less than 2 h), when administered as a conventional oral formulation, necessitates multiple 5 mg daily dosing [197],... 

In terms of drug elimination from the entire body, systemic clearance is calculated as the sum of all individual clearances from all organs and tissues (i.e., systemic CL = hepatic CL + renal CL + lung CL, and so on). Note that the elimination of the drug includes the combined processes of drug loss from the body (excretion) as well as inactivation of the drug through biotransformation.7 58 60... 

Gow PJ, Ghabrial H, Smallwood RA, et al. Neonatal hepatic drug elimination. Pharmacol Toxicol. 2001 88 3-15. 

Depending on the individual drug, elimination occurs primarily through excretion from the lungs, biotransformation in the liver, or a combination of these two methods.39 If the patient has any pulmonary or hepatic dysfunction, elimination of the anesthetic will be further delayed. 

The liver is the principal metabolic organ, and hepatic disease or dysfunction may impair drug elimination. Any alteration in the serum albumin or bilirubin levels and in the prothrombin time indicates impaired liver function. Similarly, skin bruising and bleeding tendency indicate decreased production of clotting factors by the liver. 

The most common impact of high age is via a reduced hepatic and/or renal function. In the example given, the study inclusion criteria deliberately allow the inclusion of elderly subjects with mildly impaired renal function, i.e. subjects presenting creatinine clearances of > 50 mL/min. No measures were taken to ensure that the number of enrolled elderly volunteers with normal and mild renal impairment was balanced. Such measures would have allowed an explorative insight into the impact of mildly impaired renal function, at the expense of delaying recruitment, since the recruitment of healthy elderly with mild renal impairment is more complicated. If renal elimination is believed to play a notable contribution to developmental drug elimination, then the complication of recruitment may be warranted. 

In liver disease, the likelihood of a pharmacoki-netically relevant drug-disease interaction depends on the type of drug (extent of intra-/extra-hepatic elimination, hepatic extraction ratio, protein binding) and the nature (flow, enzymatic capacity/reserve) and extent of the liver dysfunction. The likelihood of... 

Measurements such as creatinine clearance have been used successfully to adjust dosing regimens for drugs eliminated primarily by the kidneys. Measures of hepatic function have been sought using endogenous... 

In contrast to renal impairment, no obvious marker exists for characterizing hepatic function with respect to predictions of drug elimination capacity. Therefore, dose recommendations may not be as accurate for hepatic impairment as for renal impairment. 

When the extraction ratio is high, clearance is so efficient that fu. Cl int dominates the denominator of the hepatic clearance model and Q becomes negligible. As fu. Clyint then cancels out, hepatic blood flow becomes the most important factor influencing drug elimination (Panel... 

In this case, hepatic clearance is flozo limited, similar to the renal tubular excretion of p-aminohippurate. Because protein binding does not affect their clearance, drugs whose hepatic clearance is flow limited are said to be nonrestrictivehj eliminated and have extraction ratios > 0.7. 

It can be seen from Equation 7.11 that oral doses of nonrestrictively metabolized drugs should not need to be adjusted in response to changes in hepatic blood flow. Equation 7.11 also forms the basis for using AUCoral measurements to calculate so-called oral clearance" as an estimate of fuCLint. However, if renal excretion contributes to drug elimination, it will reduce AUCorai and lead to over estimation of fuCLinf unless the contribution of renal clearance is accounted for (2). 

The relationship between drug concentration and response also can be altered in patients with advanced liver disease. Of greatest concern is the fact that customary doses of sedatives may precipitate the disorientation and coma that are characteristic of portal-systemic or hepatic encephalopathy. Experimental hepatic encephalopathy is associated with increased y-aminobutyric acid-mediated inhibitory neurotransmission, and there has been some success in using the benzodiazepine antagonist flumazenil to reverse this syndrome (50). This provides a theoretical basis for the finding that brain hypersensitivity, as well as impaired drug elimination, is responsible for the exaggerated sedative response to diazepam that is exhibited by some patients with chronic liver disease (51). Bakti et al. (52) conducted a particularly well-controlled... 

Ring JA, Ghabrial H, Ching MS, Smallwood RA, Morgan DJ. Eetal hepatic drug elimination. Pharmacol Ther 1999 84 429-45. 

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