Proteins excretion barriers

Prednisolone can cause an abrupt rise in proteinuria in patients with nephrotic syndrome. A placebo-controlled study in 26 patients aged 18-68 years with nephrotic syndrome has clarified the mechanisms responsible for this (163). Systemic and renal hemodynamics and urinary protein excretion were measured after prednisolone (125 mg or 150 mg when body weight exceeded 75 kg) and after placebo. Prednisolone increased proteinuria by changing the size-selective barrier of the glomerular capillaries. Neither the renin-angiotensin axis nor prostaglandins were involved in these effects of prednisolone on proteinuria. 

Figure 5,4 Pharmacokinetics. The absorption distribution and fate of drugs in the body. Routes of administration are shown on the left, excretion in the urine and faeces on the right. Drugs taken orally are absorbed from the stomach and intestine and must first pass through the portal circulation and liver where they may be metabolised. In the plasma much drug is bound to protein and only that which is free can pass through the capillaries and into tissue and organs. To cross the blood brain barrier, however, drugs have to be in an unionised lipid-soluble (lipophilic) form. This is also essential for the absorption of drugs from the intestine and their reabsorption in the kidney tubule. See text for further details...

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

Pharmacodynamics Duration 1-4 weeks Absorption IM slow Time to peak serum levels 12-24 hours Duration 15-24 hours Absorption IM slow Distribution Poor blood-brain barrier penetration, enters breast milk Metabolism =30% hepatic inactivation Protein binding 65% Time to peak serum levels 1-4 hours Excretion Urine (60-90% as unchanged drug) Clearance Renal... 

Cisplatin shows biphasic plasma decay with a distribution phase half-life of 25 to 49 minutes and an elimination half-life of 2 to 4 days. More than 90% of the drug is bound to plasma proteins, and binding may approach 100% during prolonged infusion. Cisplatin does not cross the blood-brain barrier. Excretion is predominantly renal and is incomplete. 

Chlorpromazine is 92 to 97% bound to plasma proteins, principally albumin [5,20], It crosses the blood-brain barrier, and concentrations of the drug in the brain are higher than those in plasma [17], The relationship of plasma concentration to clinical response and toxicity has not been clearly established. Chlorpromazine and its metabolites cross the placenta and are distributed into milk [21]. About 10-12 metabolites of chlorpromazine in humans have been identified. In addition to hydroxylation at positions 3 and 7 of the phenothiazine nucleus, the N-dimethylaminopropyl side chain of chlorpromazine undergoes demethylation and is metabolized to an N-oxide or sulfoxide derivative. These metabolites may be excreted as their 0-glucouronides, with small amounts of ethereal sulfates of the mono- and dihydroxy derivatives. The major metabolites found in urine are the monoglucouronide of N-demethylchlorpromazine and 7-hydroxychlorpromazine [2]. Although the plasma half life of chlorpromazine itself has been reported to be few hours, the elimination of metabolites may be very prolonged [8, 22-24]. 

Pharmacokinetics Rapidly absorbed. Protein binding 95%. Widely distributed throughout body tissues including erythrocytes, kidneys, and blood-brain barrier. Not metabolized. Excreted unchanged in urine. Removed by hemodialysis. Half-life 2.4-5.8 hr. 

Pharmacokinetics Rapidly absorbed from the GI tract. Protein binding 84%. Crosses the blood-brain barrier. Undergoes extensive first-pass metabolism in the liver to active metabolite. Primarily excreted in urine. Half-life 14 hr. 

Pharmacohinetics Absorbed rapidly and almost completely. Distributed rapidly and extensively. Crosses the blood-brain barrier. Protein binding 95%. Metabolized in the liver. Excreted in urine and feces. Half4ife 8 hr. 

Pharmacokinetics Well absorbed from the G1 tract (not affected by food). Protein binding less than 5%. Widely distributed. Crosses the blood-brain barrier. Primarily excreted unchanged in urine. Removed by hemodialysis. Half-life 5-7 hr (increased in impaired renal function and the elderly). 

Pharmacokinetics Rapidly and completely absorbed from the GI tract. Protein binding less than 36%. Widely distributed (crosses the blood-brain barrier). Primarily excreted unchanged in urine. Not removed by hemodialysis or peritoneal dialysis. Half-life II-I5 hr (intracellular), 2-11 hr (serum, adults), 1.7-2 hr (serum, children). (Increased in impaired renal function). 

Pharmacokinetics Well absorbed from the gastrointestinal (Gl) tract. Protein binding 52%-57%. Crossesblood-brain barrier. Widely distributed. Metabolized in liverby microsomal enzyme system to inactive and active metabolites. Primarily excreted in urine. Not removed by hemodialysis. Half-life 15-40 hr. 

Mecfianism of Action A nitroimidazole derivative that is converted to the active metabolite by reduction of cell extracts otTricfiomonas. The active metabolite causes DNA damage in pathogens. Therapeutic Effect Produces antiprotozoal effect. Pharmacokinetics Rapidly and completely absorbed. Protein binding 12%. Distributed in all bodytissues and fluids crosses blood-brain barrier. Significantly metabolized. Primarily excreted in urine partially eliminated in feces. Half-life 12-14 hr. 

Stimulants are rapidly absorbed from the gastrointestinal tract after oral administration, rapidly metabolized, and excreted mainly in the urine. They are not highly protein bound, but they are lipophilic and, therefore, cross the blood-brain barrier and the placenta. 

After oral administration, it is rapidly absorbed and widely distributed into all tissues. It readily crosses blood brain barrier and is not bound to plasma proteins. It is excreted unchanged in urine. It is mainly used as adjunctive therapy in treatment of partial seizures with or without secondary generalization in adults. 

Chloramphenicol is completely absorbed after oral administration, bound to plasma protein (approximately 60%) and widely distributed in body. It crosses the blood-brain and placental barrier and shows its presence in CSF, bile and milk. It is conjugated with glucuronic acid in liver and excreted in urine. Small amount is excreted in urine in unchanged form. 

Once absorbed, foreign compounds may react with plasma proteins and distribute into various body compartments. In both neonates and elderly human subjects, both total plasma-protein and plasma-albumin levels are decreased. In the neonate, the plasma proteins may also show certain differences, which decrease the binding of foreign compounds, as will the reduced level of protein. For example, the drug lidocaine is only 20% bound to plasma proteins in the newborn compared with 70% in adult humans. The reduced plasma pH seen in neonates will also affect protein binding of some compounds as well as the distribution and excretion. Distribution of compounds into particular compartments may vary with age, resulting in differences in toxicity. For example, morphine is between 3 and 10 times more toxic to newborn rats than adults because of increased permeability of the brain in the newborn. Similarly, this difference in the blood-brain barrier underlies the increased neurotoxicity of lead in newborn rats. 

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