Multiple forms half-lives

Sahin, S. and Benet, L. Z., The operational multiple dosing half-life A key to define drug accumulation in patients and to designing extended release dosage forms, Pharm. Res., 25(12), 2869, 2008. 

Aspirin (acetylsalicylic acid, Figure 7.9) is a derivative of salicyclic acid, which was first used in 1875 as an antipyretic and antirheumatic. The usual dose for mild pain is 300-600 mg orally. In the treatment of rheumatic diseases, larger doses, 5-8 g daily, are often required. Aspirin is rapidly hydrolysed in the plasma, liver and eiythrocytes to salicylate, which is responsible for some, but not all, of the analgesic activity. Both aspirin and salicylate are excreted in the urine. Excretion is facilitated by alkalinisation of the urine. Metabolism is normally very rapid, but the liver enzymes responsible for metabolism are easily saturated and after multiple doses the terminal half-life may increase from the normal 2-3 h to 10 h. A soluble salt, lysine acetylsalicylic acid, with similar pharmacological properties to aspirin, has been used by parenteral administration for postoperative pain. Aspirin in low doses (80-160 mg daily) is widely used in patients with cardiovascular disease to reduce the incidence of myocardial infarction and strokes. The prophylaxis against thromboembolic disease by low-dose aspirin is due to inhibition of COX-1-generated thromboxane A2 production. Because platelets do not form new enzymes, and COX-1 is irreversibly inhibited by aspirin, inhibition of platelet function lasts for the lifetime of a platelet (8-10 days). 

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. 

In the single-dose adminstration studies, rivaroxaban solution was orally absorbed and reached peak plasma concentrations in 30 minutes, and when ingested in tablet form, it took two hours to reach peak plasma concentrations. In the multiple daily dose regimens, rivaroxaban took three to four hours to reach peak plasma concentration. The terminal half-life varies from 3.7-9.2 h in the multiple-dose regimen and from 7-17 h in the single-dose regimen.11... 

The dianion of TOSMIC will react readily by a [An -(- 2n] cycloaddition with nitriles to give A -unsubstituted 4-substituted imidazoles (7) (Scheme 4.2.1). These reactions also occur with other C—N multiple bonds with much more facility than with the monoanion, while other isocyanides susceptible to a-metallation can also take part [8, 9]. As mentioned above, the dilithiated derivative of TOSMIC is much more reactive than the monolithio derivative. It is also considerably more stable, e.g. the half-life of the monoanion at 20°C under nitrogen in THF-hexane is about 3h under the same conditions the dianion is still 80% recoverable after 24 h. It is possible, therefore, to prepare 4-phcnyl-5-tosylimidazole quite rapidly in 33% yield from the dianion and benzonitrile. The same product is formed only reluctantly from the monoanion. The dianion will also react even with azaaromatics (e.g. isoquinoline) with weakly electrophilic C=N bonds [9]. 

Free fatty acids, whose levels are generally raised by insulin or alcohol, influence the rate of VLDL synthesis and hence the concentration of triglycerides. About 16 g glycerol, which are mainly utilized in the liver, are released daily by lipolysis, and about 120 g free fatty acids are made available for generating energy in the heart and skeletal musculature (75%) as well as in the liver itself (25%o). These free fatty acids are bound in the plasma to albumin (50%) and lipoproteins (50%). Their extremely short plasma half-life of approx. 2 minutes emphasizes their high metabolic activity. Fatty acids are present in the plasma in saturated (no double bond) and unsaturated (various numbers of double bonds) forms. Essential fatty acids cannot be synthesized by the body, which means they must be obtained from food intake. The most important ones are multiple unsaturated fatty acids such as linolic acid (Cis-fatty acid, 2 double bonds), linolenic acid (Ci8-fatty acid, 3 double bonds), and arachidonic acid (C2o-fatty acid, 4 double bonds). Their prime function is to act as precursors for the synthesis of eicosan-oids. (s. fig. 3.10)... 

Radium 223 is promising in the treatment of bone cancer, as it has only a half-life of 11 days, short half-lives of all daughter isotopes, and produces multiple alpha particles per decay. It is now marketed in the chemical form 223RaCl2. 

Pu. The isotope Pu is the longest-lived of the plutonium- isotopes, with a half-life of 8 X 10 years. It can be produced by neutron absorption in Pu, but because of the short half-life and low concentration of Pu only minute quantities of Pu, of the order of 10" percent, are present in reactor-produced plutonium [K2]. Small quantities of Pu, as well as Pu and Pu, are present in the residues from nuclear explosions, resulting from the decay of the neutron-rich uranium isotopes and formed by multiple neutron capture in the high neutron... 

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