16 chu-c Khoi Ilfqng LLtU Ilfqng mau
3.2.1.3. Pluui llng thuy phan
Phan ling thuy phan xay ra dhuyettuong, gan, ruot va m9t so t6 chuc khac cua co th~ doi voi cac chat co hoa chirc este, amid va cac glycosid tro tim dudi anh huong cua cac esterase hoac amidase (bang 1.4). Thong thuong hoat tinh cua amidase kern hon esterase nen cac thuoc co hoa chuc amid bi thuy phan cham hon va tac dung keo dai hon, Vi du lidocain gay te dai hon procain v.v ...
Bang 1.4. M9t s6 phan (tng thuy phan
Loai philn ling Cong thuc Chatdai di~n
Thuy phan este Rr,C=O ~ R1-COOH + R2-OH Procain
R2O/ Acid acetylsalicylic
Thuy phan amid R1<,C=O
---+ ReCOOH + R2-NH2 Procainamid
R2-NH'
Thuy phan /ORz /ORz
Glycosid tim
R-CH + R3-OH
glycosid R1-CH, ---+ I ,
OR3 OH
3.2.2. Phtin. itng ehuyi'n hod phase II (Pluin. itng lien hap)
Phan ling lien hop giua thuoc hoac chat chuyen hoa cua thuoc d phase I vdi mot so chat n9i sinh xay ra co su tham gia cua cac enzym v~n chuy~n d~c hi~u (transferase). M9t so phan ling lien hQp quan trc;mg la phan ling lien hQp v{jiacid glucuronic, glycin, sulfat, glutathion v.v ...
3.2.2.1. Lien hfJpvm acid glucuronic
Lien hQp v{jiacid glucuronic la m9t trong nhfing d?ng chuy~n hoa ph6 bie'n nhat cua thuoc. Acid glucuronic chi lien hQp v{jithuoc sau khi da dtiQcho?t hoa dti{ji d?ng acid uri din diphosphat glucuronic (UDPGA) va co s\i xuc tac cua UDP glucuronyl transferase. Ezym nay co chu ye'ud gan, ngoai ra con cod th~n, ru9t. Nhfing thuoc co nhom hydroxyl, carbonyl, amin ... d~ dang lien hQp v{jiacid glucuronic t?O thanh cac san ph~m glycuro lien hQp.
Cd che' cua cac phan ling lien hQp xay ra theo cac giai do?n nhti sau:
• Tru{Je tien UDPGA dtiQct?O thanh tu glucose 1- phosphat:
Glucose I-phosphat +UDP Pyrophosphylase PP (Pyrophosphat) +UDP - Glucose
• Sau do:
UDP-Glucose +2NAD+ UDP-Glucose dehydrogenase) UDPGA +2NADH2
UDPGA +M UDP-Glucuronyltransferase) M-glucuronid +UDP
3.2.1.3. Pluui ungthuy ph/in
Phan ung thuy phan xay ra dhuyettuong, gan, ruot va mQt s6 t6 chuc khac cua co th~ d6i vdi cac chfi't co hoa chirc este, amid va cac glycosid tro tim dudi anh hudng cua cac esterase hoac amidase (bang 1.4). Thong thuong hoat tinh cua amidase kern hon esterase nen cac thuoc co hoa chuc amid bi thuy phan cham hon va tac dung keo dai hon, Vi du lidocain gay te dai hon procain v.v ...
Bang 1.4. M¢t s6 phan (/ng thuy phan
Loal phan U'ng Cong thuc Chat d,i di~n
Thuy phan este R"C=O ~ RcCOOH + R2-OH Procain
R2O'" Acid acetylsalicylic
Thuy phan amid R'<,C=O ~ RcCOOH + R2-NH2 Procainamid
R2-NH/
Thuy phan /OR2 /OR2
Glycosid tim
R-CH +R3-OH
glycosid R-CHI , ~ I ,
OH OR3
3.2.2. Pluin ling ehuyln hoti phase II (Phiin. ling lien hap)
Phan ung lien hop giira thuoc hoac chat chuyen hoa cua thu6c d phase I voi mQt s6 chfi't nQi sinh xay ra co s1,itham gia cua cac enzym v~n chuy~n d~c hi~u (transferase). MQt s6 phan ung lien hQp quan tr(;mg la ph an ung lien hQp voi acid glucuronic, glycin, sulfat, glutathion v.v ...
3.2.2.1. Lien heJpvdi acid glucuronic
Lien hQp voi acid glucuronic la mQt trong nhung d:;tng chuy~n hoa ph6 bie'n nhfi't cua thu6c. Acid glucuronic chi lien hQp voi thu6c sau khi da dUQcho:;tt hoa duoi d:;tng acid uri din diphosphat glucuronic (UDPGA) va co s1,ixuc tac cua UDP glucuronyl transferase. Ezym nay co chu ye'udgan, ngoai ra con codth~n, ru(>t. Nhung thu5c co nhom hydroxyl, carbonyl, amin ... d~ dang lien hQp voi acid glucuronic t:;tothanh cac san phftm glycuro lien hQp.
Cd che' cua cac ph an ung lien hQp xay ra theo cac giai do:;tnnhu sau:
• Trude tien UDPGA dUQct:;tothanh tu glucose 1- phosphat:
Glucose I-phosphat +UDP Pyrophosphylase PP (Pyrophosphat) +UDP - Glucose
• Sau do:
UDP-Glucose +2NAD+ UDP-Glucose dehydrogenase) UDPGA +2NADH2
UDPGA +M UDP-Glucuronyl transferase) M-glucuronid +UDP
Ghi chu: M: thu6c.
Sau khi lien hop, trong ph An cua acid glucuronic con 3 nh6m hydroxyl va
mot nh6m carboxyl nen san pham glucro lien hop (glucuronid) trd nen phan cue
manh hon (than nude), kh6 tham qua mang te bao nen thuong khong c6 tac
dung duoc IY. Ml)t khac do phan cue manh, it duoc tai hap thu qua te bao 5ng than nen duoc thai tru d~ dang hen.
D5i vdi nhfmg san pham glucuro lien hop c6 phan tl:i IUQng Ion (>500)
thuong duoc bai tiet vao mat va cudi cling lai d6 vao ruot. o ruot dudi anh hudng cua enzym- glucuronidase, san pham glucuro lien hop bi thuy phan tai tao thanh thuoc ban d:1u (hoac chat chuyen hoa ban dau) va duoc tai hap thu d ruot (chu ky gan ruot).
3.2.2.2. Lien hap udiglycin
Phan ling lien hop voi glycin thuong xay ra vdi cac thuoc c6 hoa chlic carboxyl m~ch th:1ng hol)c thdm (acid benzoic, acid isonicotinic v.v...) dUQcxuc tac bdi enzym acyltransferase t~o thanh nhung amid tudng ling. Vi dl,1trong cd th~ acid benzoic lien hQp voi glycin t~o thanh acid hipuric.
R-COOH +H2N-CH2-COOH--~ R-CO-NH-CH2-COOH
3.2.2.3. Lien hc;Jpsulfat
D~ tham gia vao qua trinh lien hQp,cac g5c sulfa:t dUQcho~t hoa duoi d~ng 3'- phosphoadenosin- 5'- phosphosulfat (PAPS). Duoi anh hUdng clla enzym sulfotransferase cac g5c sulfat dii dUQcho~t hoa se g:1n voi cac thu5c c6 cac nh6m hoa chlic alcol, phenol, amin thdm ... t~o thanh cac san ph:1m sulfat lien hQp phan cl,icm~nh d~ thai tru.
R-OH ~
R-NH2 ~
R-O-S03H R-NH-SO H3,
3.2.2.4. Lien hc;ipacetyl
Qua trinh lien hQp acetyl xay ra d5i voi cac thu5c c6 cac nh6m amin b~c I, cac hydrazid (isoniazid), sulfonamid ... duoi sl,i xuc tac clla enzym acetyl- transferase. Truoc tien cac g5c acetyl da dUQc ho~t hoa duoi d~ng acetyl coenzymA sau d6 moi lien ket voi thu5c. Ket qua clla sl,ilien hqp nay c6 th~ t~o thanh cac chfft chuy~n hoa it ph an cl,ichdn chfft m~ (d5i voi sulfonamid), l:1ng d<;mgd th~n, gay t6n thudng th~n (c6 th~ h~n che mQt phAn tac h~i bflng cach u5ng nhigu nuoc).
CH3-CO- SCoA + R-NH2 ~ R-NH-CO-CH3 + CoA-SH
3.2.2.5. Lien hc;ipmethyl (methyl hoa)
Phan ling methyl hoa xay ra d cac nh6rn chlic nang c6 chlia oxygen, nitrogen hol)c sulfur t~o nen nhung chfft chuy~n hoa thudng phan cl,ickern hdn
chat me nen it coy nghia ve mat thai trir thu6c. Tuy nhien no co vai tro trong viec sinh tang hop mot so' chat n9i sinh (epinephrin ...). Qua trinh methyl hoa can co vai tro xuc tac cua enzym methyltransferase, vdi nguon cung cap nang luong la S- adenosylmethionin. Vi du truong hop methyl hoa cua cac chat catecholamin nhu sau:
Ha--b-R > Ha-S-R
3.2.2.6. Lien hap glutathion
Glutathion la mot tripeptid trong phan til co nhom sulhydryl. Duoi anh huong cua ezym glutathion S- transferase, glutathion ph an ling vdi nhimg d~n chat halogen, epoxid... tao thanh nhirng san pham glutathion lien hop. Nhimg san pham nay tie'p tuc bi chuyen hoa tao thanh nhirng d~n chat cua acid mercapturic phan cue manh d~ dao thai ra ngoai, Phan ling lien hop glutathion coynghia rat Ion trong viec phong ngua ng9 d9Cd6i vdi mot so'chat ngoai lai.
3.3. Cam ling enzym valie che' enzym
Hftu he't cac phan ling chuyen hoa thu6c xay ra trong co th~ dac biet la d gan deu co su tham gia cua cac enzym khac nhau. Do do nhflng ye'u to' anh hUdng de'n qua trinh sinh tang hQp holItclic che' enzym d gan se anh hUdng de'n chuy~n hoa thu6c.
3.3.1. Cam itng enzym (Enzyme Induction)
Cam ling enzym la hi~n tUQngtang cudng mlic d9 enzym chuy~n hoa thu6c duoi anh hUdng Clla m9t chat nao do. Chat gay tang cudng mlic d9 enzym dUQc gQiwlachat gay cam ling enzym (enzym inducer). Cac chat khac nhau co th~ gay cam ling d6i voi nhung h~ enzym khac nhau. Trong do nhom gay cam ling ki~u phenobarbital co vai tro rat quan trQng trong chuy~n hoa thu6c. Cac chat trong nhom nay co tac d1,lngtang sinh luoi n9i ma gan d:1n de'n tang cudng tang hQp m9t so' enzym chuy~n hoa thu6c d gan nhu cyt P450, glucuronyl transferase, glutathion-S-transferase, epoxid hydrolase ... Vi cam ling enzym lien quan de'n tang hQp protein moi nen anh hUdng t6i da clla no th~ hi~n sau 2- 3 tuftn k~ tu khi dung chat gay cam ling va tie'p t1,lCkeo dai m9t vai tuftn l~ k~ tu khi ngung chat gay cam ling. Ke't qua clla cam ling enzym la tang cudng sinh tang hQp enzym gan nen lam tang chuy~n hoa, rut ngiin thdi gian ban thai clla thu6c do do anh hUdng de'n tac d1,lngclla thu6c:
- Phftn IOncac trudng hQp sau khi chuy~n hoa thu6c bi giam holItcmat tac d1,lngnen trong nhung trudng hQpnay cam ling enzym lam giam holItcmat tac d1,lngclla thu6c.
- DDi vdi mot sDthuDc chi sau khi chuyen hoa mdi co tac dung hoac tang dQctinh thi cam ling enzym lam tang tac dung hoac tang dQc tinh cua thuoc.