Studies on the Absorption of Subcutaneously Implanted Tablets of Hexoestrol
S. J. Folley
Proceedings of the Royal Society of London. Biological Sciences
1. The large com pressed tab lets o f pure hexoestrol used, possess a 'la b ile ' com ponent (that m ay or m ay n o t be located in th e surface zone), w hich is quickly lo st on subcutaneous im plantation or incubation w ith blood p lasm a or w ater. The rem aining surface is m uch less soluble. T ablets im planted su bcutaneously after h avin g suffered loss o f th e 'la b ile ' com ponent, because o f previous in vivo im p lan tation or incu b ation w ith blood plasm a or w ater, undergo
... absorption in a given tim e th a n unused tab lets. 3. In consequence o f (1), absorption curves for 1000, 500 and 250 m g. ta b lets in th e bovine, goat, rabbit, guinea-pig, rat and pigeon show tw o phases, an in itial phase o f rapid absorption due to th e loss o f th e 'la b ile ' com ponent, after w hich th e curves bend sharply and thereafter pursue a linear course (linear phase). On th e other hand, curves for 50, 25 and 15 m g. tab lets in th e rat are linear and pass through or v ery near th e origin. D uring th e im p lan tation period, h exoestrol ta b lets (and also ta b lets o f steroid horm ones) becom e infiltrated w ith structures (ghosts) com posed o f insoluble protein, p robably a scleroprotein, form ed b y reaction betw een th e horm one and soluble ^protein present in th e tissue fluids. G hosts are quite d istin ct from th e fibrous-connective tissu e capsules w hich are often form ed round ta b lets in vivo. 5. G hosts are also form ed in h exoestrol ta b lets im m ersed in b lood serum or plasm a and protein solutions. 6. A bsorption valu es (apparent), determ ined b y losses in w eigh t during im p lan tation , are in each case lower th an th e true valu e b y th e w eigh t o f th e gh ost and, on extrap olation , true absorption curves m ake larger intercepts on th e v ertical axis th a n apparent curves. 7. In consequence o f (6) th e curves for sm all ta b lets in rats are in reality o f th e sam e form as those for larger tab lets, th ou gh here th e difference m ade b y th e gh ost correction is sm all. Such curves, w hen corrected for gh ost form ation, th u s m ake on ly sm all in tercep ts on th e vertical axis indicating th a t th e 'la b ile ' com ponent is m uch less im portant in th e sm all tab lets th an in th e 250, 500 and 1000 m g. classes. The absorption rate during th e linear phase is th e characteristic absorption rate for an y given w eight class o f tab let. A bsorption rates per m m .2 for ta b lets o f various sizes in different anim als are ap p roxim ately con stan t, provided th e ta b lets are n o t to o big in relation to th e size o f th e anim al, show ing th a t absorption rate is proportional to surface area. W ith large ta b lets in th e rat, absorption (linear phase) is either v ery reduced or non -existen t. T his m a y be due to satu ration o f th e b o d y w ith h exoestrol absorbed during th e initial phase. 9. T he effect, if a n y , o f gh ost form ation on th e linear absorption rate rem ains obscure. The m ethod of sex hormone adm inistration by subcutaneous im plantation of solid tablets, first described by Deanesly & Parkes (1937), provides a means whereby a small, b u t w hat is most im portant, continuous dosage over prolonged periods m ay be ensured. The technique has now firmly established itself, and numerous reports attesting to its usefulness both for experimental and clinical purposeis have been reviewed by W arwick & Parkes (1940). * I n a g r e e m e n t w it h F o r b e s ( 1941), w h o sp e c ific a lly in v e s tig a t e d t h e p o in t , th is w o r k p r o v id e d n o e v id e n c e t h a t a b so r p tio n r a te is in flu e n c e d b y t h e s e x o f t h e h o s t.