,... •• tN.I. .
(1,n
PharmM'OlIl~I .
Dna Iatencd,.
18 t6r. 471-134. 1990
0 31 2- S%3f90/000f>..()4 7!/S06 SOlO
CI ADIS p~ Llmllro All nJ!1u rn;cr"ro (;1'1rup ........... . ......... .481 2.5 C'onll;Wleroll,b .................................... .481 2.6 A)cohol ............................... ........... .481 ... 48) 2. 7 Other Drugs .................. . ] . C'onc::IUSlons .......................... .... 481
'" '" '" '" ". ".
Oral contrace pti ve steroids are used by an estimated 60 to 70 million women worldWide. Over Ihe past 20 years there have been both case repons and clinical studlcs on the tOPIC of drug IntemCIIOnS with IhC'K agents. Some of the ml el1lCtlons are of defimte therap(u\lc relevance ..... hereas others can be dlscount«l as being of no clinical SIgnIficance. PharmacologIcal interactions belwC'tn oral eontracepti"e steroIds and Olher com· pounds may be of 2 kInds.: (a) drugs ma y Irnp.:m Ihe efficacy of oral eontracepl"'e ster· olds. \cadmg 10 breakthrough bleedmg and prcananey (m a few cascs. the ae\! Vl\y of Ihe contracepllve IS enhancro): (bl 01111 contmccpll\e stero,ds rna) Interfere wllh the mrtabollsm of other drugs. A number of an lleonvulsants (phenooorbliai. phenytOin. ea roomalepmel arc enzyme· induemg agents and thereby Increase the cleamnce of Ihe oml contrace pti ve steroids. Valprole aCid has no enzymC-IndUClng propcnles. and thus women on thiS antIconvulsant ca n rely on theIr low dose oral contracepllve sterOIds for contraeepll\e prOlrcuOn. Re-
Urug Inl"'I'3(1I0ns "llh Oral
473
(onll'3fi.'ptl,e~
'IoC'ar(hers arc nu" ix'glnnlng to unra, i.'1 the molecular baSIS of thiS Inl\:raClIon. "uh e'ldence of sp.:cllic form~ ofc~tochrome P450 (P4S011C and Ili A gene families) being 10dlll:ro h~ phenobarhltal. RifampIcin. Ihe antltubc.'rculous drug. also Illdun's a c~ tochrome P-I50 .... hKh I~ a product of th" P4501l1A gelle subfamll}. ThiS ISOI)me IS one of the major forms m'Ol-cd III ~-h~dro\}latlon ofC"thln}lcstradlol. Broad ~p.:'lrUI11 anllblOllcs ha,,' Ill'cn lmplleatmularl}. there IS no e\ldence Ihat smoi.mg allers Ihe pharmaeoi.melles of oral ,'onlra,-cpllH' slerold\ Th,'''''' agenl\ art' no" ",dl documellted as Ill'mg able 10 ahl.'T Ihe pharm3cokmelles of olh,'r ("t)l1C(lmltantl~ admlnISI"T\'d drugs Th ... d(,3ran,'e of a lIumber of benl.odlalepln"S undergOing u\ldal1on Irhlordla/epo\ ...tc:. alprOllolam. d,alepam) alld 1I,Iro froueIIUII I nl1rafepan1l. theuph' IIlnl.'. pT-,,0,1 sJX'clficall~ inhIbIted > ~ of the aetl\lI~ In human II\er microsom('s. Th(' "orJ..mg h~ pothe\ls. thl'n. has \0 be th:lI phenobarbital and Table II. Area under Ihe 24·hour ~Iasma concentral,on·l,me curve lAUe) 101 elh,nyleslrad,ol (EE2) and levooorge511el (LNG) 'n pal,ents tal"ng e,the. phenylOIrl carbamazep,ne or val~rOlC
".
~~
"...
EE2 AUe ("giL' n)
lmol C()f1trOl
,,
Phenyto,n
'SO
'00 '00 '00
3
•5
300 300
6 Mean
".,
10" 0332
0208
'"
50'
0411° • 0132
336 19'
,
0326 0234
0'"
C,rbt;muep,ne
,
'00
"33
o 6JO
300
1024
0960
3
600
O7SO
0451
•Mean
600
-so
""" ""
""
0788
09" 1075
• 0466
VeiprOI(: ,cod
,
'00 '00 '00 .00 .00 .00
3
•5 6 Mean
SO
096. 0981
0758
"3' OS., 0880 0267
.., Oa,ly dOse 01 anl'ep,lept'c , 005
C()f1UOI
0672" • 0211
0873 1 112
""
..
"" '01 '"22' -
,.
352
'09
'" '59 '"
"
MCl a UTI
(P45OIA2) (P45OIIAI )
PBJa PBIa
(P4501181) (P45OIIC6)
53000 "500
Band I
"500
Bano 2 Sand 3 OeDr,soqUlne (P4501I0) (P45OIIEI) (P4501IIA) (P45OIVAI )
1eSl
'26
a
~
Apparen,
EE,
"WI
Band I Band I Band I
51000 51000 52500
021 029
'"
052 "3
075"
51500
". 005
.",,"
"500
010
51000 51500
062" 078°
Band I
NO NO
001 037
Band I
Band 2
51000
001
D P 0001 Aoore"'o1/'ons MWt · molecular wergn! NO· not determ,ned
'"
13' 59
'" 32'
195°
- 93
105 87
'"
'19
138°
-
"
'315 81 33' 253
0441
0977 ~ 0319
Bands r6en\lloed
P82e P452
LNG AUe (..gIL · n)
'I' ", 10' ".
0303
0956 0944 0785 0710 0740
0122
- SO
teSI
Teble 111. Spearman 5 rank correlations Oo8lWeen eln,nyIeSlra' doOl (EE2) melaDohsm and the levels or P450 lorms ,n numan I,ve. In certa,n cases more than one Dand was recogn,sed by the ant,bod,es used In tne case 01 P45011C In,s ,5 conS'Slent w,lh tne known ex~resSIOn Or several members 01 tnlS gene lam'ly III numan liver
29'
- 38
other ant lcon\ ulsant drugs can Induce thiS 150z~ me and henee Increase Ihe rale and extent of 2· h)dro\)latlon. -\ddllional studies In the same area ha\e bt.--en performed b) Ball el al. (1989). "ho ex· amlned human Incrs for a \anet~ ofenz)me ae11\II It,'S IncludIng e t hln~lestradlOl 1-h~drox)lasc. Thl' h,ghest ethrn~leslradioI1-h~dro\~lase actnlt) "as found In Ihe Incr of a subject "ho had ree('IH'd phenobarbital and phcn~101n for mOTe than 1S ~ears. In olher studies. antibodies raised In rabbHS 10 r:l.I hepatIC c~tochrome P450 iSOl)meS "ere used to rnhlbll the e t hln~lestradlol 2.h)dro\)laS(" aetl\ II~ of human Incr samples. POSSible correlalIOns bet"een the protems recogntsed b) the anllbodIes and 1·h}drox)lal1on rate "eTC determined (table III ). TheS(" e\penments pro\ Ide C\ Idenee Ihal 1.h~d ro\) lallon of cthm~ lestradlol IS catal}scd b) c~tochroml's from the P450Il C. NSOII E and P..I,OI II-\ scne subfam ihcs: some of these arc indUCIble b~ the anllcon\ulsants menlioned ab_ HO\ll'H'T. Cra\\lord 1.'1 al. (1IJJ:o;I) namlnl'd J. 101J.1 of \11 oralt'ontran'p11\1.' u~cr\ (IU~ \mo"'cr~; :!(N nonsmoh-T5) and found no slgmficant dlfli:rcncc 10 plasma l'lhm~l ,,'!>tradm) (or klonorgl'slrd) ('onccntrallOn ... ,\ jOrl' rl·n'nll~. h.anarI..Ov. skl 1.'1 al. (1'n ~
"r
"""II,(
~nI! \I "I,,'ulu f'harm:hol.'S, n m m mJII I).u, \"',ahul"m 1oI. ,·"c"~ of "lh'n'k\lf~J'ol an d k,,,n"'''''I'ct ,n .dall"n 10 ,mo l ln,. U",,,al I'halm J
(1,n
PharmM'OlIl~I .
Dna Iatencd,.
18 t6r. 471-134. 1990
0 31 2- S%3f90/000f>..()4 7!/S06 SOlO
CI ADIS p~ Llmllro All nJ!1u rn;cr"ro (;1'1rup ........... . ......... .481 2.5 C'onll;Wleroll,b .................................... .481 2.6 A)cohol ............................... ........... .481 ... 48) 2. 7 Other Drugs .................. . ] . C'onc::IUSlons .......................... .... 481
'" '" '" '" ". ".
Oral contrace pti ve steroids are used by an estimated 60 to 70 million women worldWide. Over Ihe past 20 years there have been both case repons and clinical studlcs on the tOPIC of drug IntemCIIOnS with IhC'K agents. Some of the ml el1lCtlons are of defimte therap(u\lc relevance ..... hereas others can be dlscount«l as being of no clinical SIgnIficance. PharmacologIcal interactions belwC'tn oral eontracepti"e steroIds and Olher com· pounds may be of 2 kInds.: (a) drugs ma y Irnp.:m Ihe efficacy of oral eontracepl"'e ster· olds. \cadmg 10 breakthrough bleedmg and prcananey (m a few cascs. the ae\! Vl\y of Ihe contracepllve IS enhancro): (bl 01111 contmccpll\e stero,ds rna) Interfere wllh the mrtabollsm of other drugs. A number of an lleonvulsants (phenooorbliai. phenytOin. ea roomalepmel arc enzyme· induemg agents and thereby Increase the cleamnce of Ihe oml contrace pti ve steroids. Valprole aCid has no enzymC-IndUClng propcnles. and thus women on thiS antIconvulsant ca n rely on theIr low dose oral contracepllve sterOIds for contraeepll\e prOlrcuOn. Re-
Urug Inl"'I'3(1I0ns "llh Oral
473
(onll'3fi.'ptl,e~
'IoC'ar(hers arc nu" ix'glnnlng to unra, i.'1 the molecular baSIS of thiS Inl\:raClIon. "uh e'ldence of sp.:cllic form~ ofc~tochrome P450 (P4S011C and Ili A gene families) being 10dlll:ro h~ phenobarhltal. RifampIcin. Ihe antltubc.'rculous drug. also Illdun's a c~ tochrome P-I50 .... hKh I~ a product of th" P4501l1A gelle subfamll}. ThiS ISOI)me IS one of the major forms m'Ol-cd III ~-h~dro\}latlon ofC"thln}lcstradlol. Broad ~p.:'lrUI11 anllblOllcs ha,,' Ill'cn lmplleatmularl}. there IS no e\ldence Ihat smoi.mg allers Ihe pharmaeoi.melles of oral ,'onlra,-cpllH' slerold\ Th,'''''' agenl\ art' no" ",dl documellted as Ill'mg able 10 ahl.'T Ihe pharm3cokmelles of olh,'r ("t)l1C(lmltantl~ admlnISI"T\'d drugs Th ... d(,3ran,'e of a lIumber of benl.odlalepln"S undergOing u\ldal1on Irhlordla/epo\ ...tc:. alprOllolam. d,alepam) alld 1I,Iro froueIIUII I nl1rafepan1l. theuph' IIlnl.'. pT-,,0,1 sJX'clficall~ inhIbIted > ~ of the aetl\lI~ In human II\er microsom('s. Th(' "orJ..mg h~ pothe\ls. thl'n. has \0 be th:lI phenobarbital and Table II. Area under Ihe 24·hour ~Iasma concentral,on·l,me curve lAUe) 101 elh,nyleslrad,ol (EE2) and levooorge511el (LNG) 'n pal,ents tal"ng e,the. phenylOIrl carbamazep,ne or val~rOlC
".
~~
"...
EE2 AUe ("giL' n)
lmol C()f1trOl
,,
Phenyto,n
'SO
'00 '00 '00
3
•5
300 300
6 Mean
".,
10" 0332
0208
'"
50'
0411° • 0132
336 19'
,
0326 0234
0'"
C,rbt;muep,ne
,
'00
"33
o 6JO
300
1024
0960
3
600
O7SO
0451
•Mean
600
-so
""" ""
""
0788
09" 1075
• 0466
VeiprOI(: ,cod
,
'00 '00 '00 .00 .00 .00
3
•5 6 Mean
SO
096. 0981
0758
"3' OS., 0880 0267
.., Oa,ly dOse 01 anl'ep,lept'c , 005
C()f1UOI
0672" • 0211
0873 1 112
""
..
"" '01 '"22' -
,.
352
'09
'" '59 '"
"
MCl a UTI
(P45OIA2) (P45OIIAI )
PBJa PBIa
(P4501181) (P45OIIC6)
53000 "500
Band I
"500
Bano 2 Sand 3 OeDr,soqUlne (P4501I0) (P45OIIEI) (P4501IIA) (P45OIVAI )
1eSl
'26
a
~
Apparen,
EE,
"WI
Band I Band I Band I
51000 51000 52500
021 029
'"
052 "3
075"
51500
". 005
.",,"
"500
010
51000 51500
062" 078°
Band I
NO NO
001 037
Band I
Band 2
51000
001
D P 0001 Aoore"'o1/'ons MWt · molecular wergn! NO· not determ,ned
'"
13' 59
'" 32'
195°
- 93
105 87
'"
'19
138°
-
"
'315 81 33' 253
0441
0977 ~ 0319
Bands r6en\lloed
P82e P452
LNG AUe (..gIL · n)
'I' ", 10' ".
0303
0956 0944 0785 0710 0740
0122
- SO
teSI
Teble 111. Spearman 5 rank correlations Oo8lWeen eln,nyIeSlra' doOl (EE2) melaDohsm and the levels or P450 lorms ,n numan I,ve. In certa,n cases more than one Dand was recogn,sed by the ant,bod,es used In tne case 01 P45011C In,s ,5 conS'Slent w,lh tne known ex~resSIOn Or several members 01 tnlS gene lam'ly III numan liver
29'
- 38
other ant lcon\ ulsant drugs can Induce thiS 150z~ me and henee Increase Ihe rale and extent of 2· h)dro\)latlon. -\ddllional studies In the same area ha\e bt.--en performed b) Ball el al. (1989). "ho ex· amlned human Incrs for a \anet~ ofenz)me ae11\II It,'S IncludIng e t hln~lestradlOl 1-h~drox)lasc. Thl' h,ghest ethrn~leslradioI1-h~dro\~lase actnlt) "as found In Ihe Incr of a subject "ho had ree('IH'd phenobarbital and phcn~101n for mOTe than 1S ~ears. In olher studies. antibodies raised In rabbHS 10 r:l.I hepatIC c~tochrome P450 iSOl)meS "ere used to rnhlbll the e t hln~lestradlol 2.h)dro\)laS(" aetl\ II~ of human Incr samples. POSSible correlalIOns bet"een the protems recogntsed b) the anllbodIes and 1·h}drox)lal1on rate "eTC determined (table III ). TheS(" e\penments pro\ Ide C\ Idenee Ihal 1.h~d ro\) lallon of cthm~ lestradlol IS catal}scd b) c~tochroml's from the P450Il C. NSOII E and P..I,OI II-\ scne subfam ihcs: some of these arc indUCIble b~ the anllcon\ulsants menlioned ab_ HO\ll'H'T. Cra\\lord 1.'1 al. (1IJJ:o;I) namlnl'd J. 101J.1 of \11 oralt'ontran'p11\1.' u~cr\ (IU~ \mo"'cr~; :!(N nonsmoh-T5) and found no slgmficant dlfli:rcncc 10 plasma l'lhm~l ,,'!>tradm) (or klonorgl'slrd) ('onccntrallOn ... ,\ jOrl' rl·n'nll~. h.anarI..Ov. skl 1.'1 al. (1'n ~
"r
"""II,(
~nI! \I "I,,'ulu f'harm:hol.'S, n m m mJII I).u, \"',ahul"m 1oI. ,·"c"~ of "lh'n'k\lf~J'ol an d k,,,n"'''''I'ct ,n .dall"n 10 ,mo l ln,. U",,,al I'halm J
