Alteplase (BAN, USAN, INN) ; Activase (R)
8.1. Alteplase (BAN, USAN, INN) ; Activase (R)
Recombinant Tissue-type Plasminogen Activator ; rt PA ; Form
Molecular Weight Non-glycosylated
Molecular Formula
C 2736 H 4174 N 914 O 824 S 45 64, 497.9 Glycosylated
C 2569 H 3894 N 746 O 781 S 40 59, 008.4 USP ;
Description : Alteplase (activase) in a glycosylated protein of 527 residues having the amino acid sequence of human tissue plasminogen activator ( τ -PA) and produced by the recombinant DNA technology.
Note : The name may be elaborated on the label by sets of initials mentioned in paren- theses so as to indicate the specific method of production, example :
(rch) : indicates the production from the genetically-engineered Chinese hamster ovary cells.
Storage : Alteplase need to be stored preferably at – 20°C or even below in perfectly sealed containers.
In fact, various elaborated studies meticulously carried out by researchers revealed vital and important observations with regard to the ‘stability conditions’ of alteplase as detailed below :
GENETIC RECOMBINATION
Lee et. al. 1990* : concluded that ‘alteplase’ must not be mixed in the same container with me- dicinal compounds such as : dobutamine, dopamine, heparin or glyceryl trinitrate, because there was indeed ample available evidence of incompat-
ibility ;
Frazin** (1990) : observed that dilution of a proprietory preparation of alteplase (Activase) to
0.09 and 0.16 mg . mL –1 with 5% (w/v) glucose injection distinctly resulted in the precipitation of the drug. Frazin made the following two observations :
(a) Alteplase is formulated with arginine as a solubilizing agent, and dilution with 5% (w/v) glucose to concentration below 0.5 mg of alteplase per mL usually makes precipitation possible, and
(b) Dilution with 0.9% (w/v) NaCl (i.e., Normal Saline Solution) is possible to concentrations as low as 0.2 mg. mL –1 before the precipitation becomes a risk.
Units : The activity of alteplase may be measured in terms of International Units (IU) by employing the 2nd International Standard for the Tissue Plasminogen Activator established in 1987, although it is an usual practice to express the doses by weight. The Specific Activity of alteplase is 580 000 IUs. mg –1 .
Pharmacokinetics : It has been duly observed that alteplase gets cleared from the plsma, chiefly via metabolism in the liver.***
Uses and Mechanism of Action : The various applications and possible mechanism of action of ‘alteplase’ are as follows :
(1) It is a thrombolytic agent, which is a predominant representative of a single-chain form of the endogenous enzyme tissue plasminogen activator meticulously produced by the
recombinant DNA technology.
Very much similar to the endogenous tissue plasminogen activator, it converts fibrin-bound plasminogen to the corresponding active form of plasmin, thereby causing in marked and
pronounced fibrinolysis and dissolution of clots. (2) Alteplase has almost negligible effect upon the circulating, unbound plasminogen ; and
hence, may be termed as a fibrin-specific agent. It was perhaps thought that fibrin specificity could be an absolute necessity for minimising the prevailing risk of ensuing haemorrhage intimately associated with the application of thrombolytics ; although the latest fibrin-
specific drugs usually give rise to appreciable bleeding in comparison to the non-specific thrombolytics.
(3) Alteplase is employed very much akin to steptokinase both in the management and treat- ment of thrombo-embolic disorders, specifically the myocardial infarction and venous
thrombo-embolism.****
* Lee CY et al. Visual and Spectrophotometric determination of Compatibility of alteplase and Streptokinase with other injectable drugs. AmJ. Hosp. Pharm. 47 : 606-8, 1990.
** Frazin BS . Maximal Dilution of Activase, AM J Hosp. Pharm. 47, 1016, 1990. *** Krause J : Catabolism of tissue-type plasminogen activator (t-PA) its variants, mutants and hybrids,
Fibrinolysis, 2, 133-42, 1988. **** Deep-vein thrombosis and pulmonary embolism.
PHARMACEUTICAL BIOTECHNOLOGY