Pharmacokinetic Drug Interactions

Cion. Phar m aco ~ ,"ci 181:1; 131·1~. 1990 OJ 11·S96J:'90/OOO:.(I1 J liS I0.00/0 e AOIS I're~~ L,m a M A ll "8h' ~ ",~" Nl

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Pharmacokinetic Drug Interactions with Phenytoin (Part 11) Roger L. Natioll. AI/all M. Emlls and Robert W. Milne School of Pharmaq . South Australian Institute of Teertoglio et a!. 1984). The phenytoin-induced alteration in prednisolone pharmacokinetics is associated with a reduced biological responsiveness to a given dose of the glucocorticoid. For example, during phenytoin treatment prednisolone had a reduced suppressive effect on the morning plasma hydrocortisone con-

C/m. Phurmaco/..m('/. 18 (2) 1990

centralion in healthy volunteers (Petereit & Meikle 1977) and in renal transplant patients (Gambertoglio el a!. 1984). Moreover, Frey & Frey (1984). using the inhibition of the mixed lymphocyte reaction as a modd, found that phenytoin pretreatment decreased the immunosuppressive activity of plasma prednisolone as a function of time after administration. while the unbound prednisolone concentration required to produce one-half the maximal inhibition was unaffected. Thus, enzyme induction by phenytoin decreased both the unbound prednisolone concentration and the glucocorticoid effectiveness after a standard dose of prednisolone (Frey & Frey 1984). These findings suggest that careful consideration must be given to the choice of prednisolone dose in renal transplant patients and others in whom prednisolone and phenytoin arc to be coadministered (Frey & Frey 1984; Gambertoglio et a!. 1984; Petereit & Meikle 1977). Methylprednisolone The limited information available suggests that phenytoin increase5 the clearance and decreases the half-life of methylprednisolone (Stjemhoim & Katz 1975). Dexamethasone 'Low-dose' and 'high-dose' dexamethasone suppression tests are used in the differential diagnosis of Cushing's syndrome. It has been reported that patients without Cushing's syndrome who are receiving long tenn phenytoin therapy have less than normal suppression of plasma corticosteroid concentration and urinary 17-hydroxycorticosteroid excretion after a 'low-dose' test but nonnal suppression after the 'high-dose' test, suggestive of Cushing's disease (Jubiz et al. I970b). It appears that this potential for misdiagnosis arises because phenytoin increases the clearance and decreases the half-life of dexamethasone, which is cleared almost entirely by the nonrenal route (Tsuei et a!. 1979). As a result, in patients receiving phenytoin. lower than normal plasma dexamethasone concentrations occur during the 'low-dose' test, leading to reduced negative feedback on the pituitary gland

Pharmacokmet1c Interact10ns wllh Phenytoin

(Haque et a1. 1971). Thus. dexamethasone suppression tests for the diagnosis of Cushing's syndrome must be interpreted wllh great care in patients receiving phen~ toin (Jublz et al. 1970b). A s1milar caveat apphes when dexamethasone suppression is used as a et st ofhypothalamic-pllu1taf)-adrenal axis function In ps}chl3tTlc pallents and as an a1d In the diagnosIs of depression (Low~ & h1cltzer 1987). Phen~tOln and dexamethasone arc commonl) used together in neurological and neurosurgical patients. For e'>ample. with the craniotomy procedure. JI is common for phen} tOIn and dexamethasone to be g1ven concurrently. the former drug to reduce thc Incidence of seizures and the laller to help control intracranial pressure. Chalk et al. (1984) studied the disposition of dexamethasone administered orally and Intra\"enousl~. on separate occasions. in I group of 6 neurological or neurosurgical patients who were also receiving phenytoin and in a second group of9 patients who were not: I patient was studied both before and during phenytoin treatment. The mean ( ± SO) systemiC plasma clearance of dexamethasone was 271 :!. 129 ml/ h/ kg In those not receiving phenytOin and 798 :::': 479 ml/h/ kg In those receiving the antlcon\ ulsant. while the corresponding oral bioavailabJiI\}' eSllmates were 0.84 ± 0.23 and 0.33 :::': 0.33. respectl\el~. Both the s~stemlC clearance and the oral blOa\"ailabilit} differed slgmficantl~ between the 2 groups of pa\lents. These data arc consistent wllh phen}toin treatment ha\ing convened de."amethasone from a drug of rclati\cl} low hepatIC' extracllon (Tsuel et al. 1979) to one of relatively high hepallc extraction as a result of induction of the hepatic enzymes In\ol\ed In dexamethasone biotransformation. As pointed out by Chalk et al. (198~). the Inter· action between dexamethasone and pheny tOIn in neurosurgical patients ma~ be \ef) Imponant Clinically lJc(:ause dexamethasone may be administered in life-threatening situations. Solely on the bas1s of the magnitude of the difference in oral bioavailabilit). Chalk et al. (198~) suggested that patients receiving phenytoin rna) require oral dexamethasone doses several times larger than those reqUired by patients not receiving the anti-

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convulsant. However, Chalk et al. (1984) have probably underestimated the magnitude of the oral dose difference required between the 2 populations. lJc(:ause the difference in oral bioavailability will In turn underestimate the magnitude of the difference in AUe after oral administratIOn (Wilk1Oson & Shand 1975). Finally. McLelland and Jack (1978) reponed a case in .... hich phenytom appeared to increase dexamethasone dose requirements m a neurosurgical patient. Metyrapone Metyrapone. an mhibitor of adrenal I llihydrox)lase. is used as a d1agnost1c agent for assessing antenor pllu1taf) function. In a healthy individual. the administration of metyrapone in a standard oral test dosage regimen leads to a decrease In h)droconisone producllon wllh an asSOCiated decrease m plasma hydrocortisone concentrallon. Subsequently, there is a compensatory flse In corticotrophin release from the anterior pituitary. resulting in increased plasma concentrations of Il-desoxyhydrocortisone and increased urinaf) excretion of 17-hydrox)conlCoids. However. subjects with normal anterior pituitary function who are receiving phenytoin are known to exhibit a subnormal response to the standard oral metyrapone test (Meikle et al. 1969). With the standard test. plasma met)rapone concentral10ns have been shown to be decreased markedl) in subjects treated .... I\h phenytoin (Jubiz et al. 1970a: Meikle et al. 1969). and this was associated with subnormal plasma and urinary sterOId responses lJc(:ause the plasma metyrapone concentrallons achieved were madequate to inhibit adrenal ll.d-hydro.xylase (Me1kle et al. 1969). Doubling the oral dose of metyrapone in phenytOin-treated subjects led to plasma concentrations of met)rapone. corticotrophm and ll-desoxyh}droconisone which were not different from those secn in control subjects given the standard oral dose of metyrapone (Meikle et a1. 1969). Since only a small fraction of a met)raponc dose is cleared as unchanged drug in urine (Hannah & Sprunt 1969). and assummg that phenytom does not affect the oral mel}'rapone absorption. II appears that phen)-

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loin increases the hepatic clearance of the drug. An interesting point is that when metyrapone was administered as a 4-hour intravenous infusion, there was no difference between phenytoin-treated and untreated subjects in the end-infusion plasma me· tyrapone concentration or the half-life of metyrapone determined post infusion (Meikle el al. 1969). In keeping with Ihe similar exposure to intrnvenaus metyrapone between the 2 groups, the phenytoin-treated subjects exhibited normal plasma and urinary steroid responses (Meikle el a!. 1969). Clearl y. erroneous results with the oral metyrnpone test may occur in patients laking phenytoin . In view of the substantially lower plasma metyrapone concentrations after oral administration of the standard leSI in phenytoin-treated subjects. Meikle and co-workers (1969) were puzzled by the normal character of the concentrations after intravenous administration in subjccts rettiving the anticonvulsant. However. these findings are consistent with the fact that metyrapone appears to ha ve a relatively high hepat ic extraction ratio. as calculated from the data of Meikle et al. (1969). For such a drug, systemic clearance and plasma concentrations following intravenous administration will be sensitive to variations in hepatic blood now-rate but relatively insensitive to variations in hepatic intrinsic clearance. However, plasma concentratIons following ornl administration will be very sensitive to alterations in the latter (Wilkinson & Shand 1975), as may occur with coadministrntion of a drug which induces hepatic drug-metabolising enzymes. This illustrates the importance of experimental design in pharmacokinetic drug interaction studies. 2.1.5 CardioaCtlw' Agl'nis Digoxin Rameis (1985) reported that coadministration of phenytoin to healthy volunteers caused a significant reduction in the elimination half-life of digoxin and a significant increase in its total clearance. Because the renal clearance of digoxin was not affected, it was concluded thai phenytoin increased its hepatic clearance. Halawa (1985) also

ClIIl. PharmacoJ.;I1IN

/8 (1) 1990

investigated the possible interaction between digoxin and phenytoin. While there was a trend towards higher digoxin clearance during phenytoin treatment. the difference was not significant. Digoxin has a low therapeutic index and. therefore, patients rettlving this drug should have plasma concentrations of the drug monitored if phenytoin is initiated or discontinued. Digitoxin Compared with digoxin, digitoxin is metabolised extensively and only a small fraction of an administered dose is excreted in urine as unchanged drug. It might be expected, therefore, that digitoxin clearance would be more sensitive to induction of microsomal enzymes. There has been I case report in which there was a decrease in the steady-state plasma digitoxin concentration when phenytoin therapy was commenced; when the treatment was discontinued. the plasma digitoxin level increased (Solomon et al. 1971). Quinidine The concomitant administration of phenytoin has been reported \0 cause a decrease in plasma quinidine concentration in patients with ventricular arrhythmias (Data et al. 1976; Urbano 1983). In other studies. both the half-life and AUC of quinidine, following a single oral dose. were decreased substantially during phenytoin treatment (Data et al. 1976; Halawa 1984). an effect attributed to increased metabolic clearance of quinidine (Data et al. 1976). The magnitUde of the interaction led Data and co-workers (1976) to caution that a patient who is well con trolled on quinidine may become quinidine toxic if phenytoin is discontinued, or scrious arrhythmias may emerge if phenytoin is startt.:d. Mexlletine Having observed unexpectedl y low plasma mexiletine concentrations in 3 patients treated concurrently with mexiletine and phenytoin, Begg et a1. (1982) conducted a pharmacokinetic drug interaction study in 6 healthy volunteers who were given a single oral dose of mexiletine before and

Pharmacoklnc\lC [ntcracILons "uh Phrn}toln

after I week's admi nistration of phenytoin JOOmg daily. Pretreatmen t with phenytoin resulted in a signi fican t red uction in the half-life and AUe of mexi letine: the mean value of each was ap proxi. mately halved. Because mexiletine is extensively metabohsed. it was suggested by Begg and co-workers ( 1982) that the most likely explanation for the interaction was indUCIion of the hepatic mixedfunc tion oxidase system. Segg et aL ( 1982) felt that thts interacllon is IIkel) to be clinically important because of its magnitude and because II was firs t observed in the clinical setllng. LidocalOe (Lignoc31Oe) Perucca and Rlchens (1979b) studied the pharo macokinetics of lidocaine. a drug cleared predominantly b~ hepatic biotransformation. in 6 patients receiving long term antiepilcptic drug therapy and in 6 healthy volunteers. [n the single epileptic patient who was receiving phenytoin as the only anticonvulsant medicallon. systemic serum clearance of lidocaine following intravenous administration was marginally higher than the mean clearance for the volunteers. However. thiS difference in serum clearance would underestimate the difference 10 systemic blood clearance because the blood 10 plasma concentration ratio of lidocaine was lower 10 patients receiving phenytoin (Roul. ledge CI al. 1981). After oral admlOlstrallon of II· docaim'. the apparent effect of phenytolO was much greater: In thc single patient on phenytoin alone as anticonvulsant therapy. AUC and oral bloaVal labi lity of lidocaine were only aboul 25% of the mean values observed in the healthy volun teers. while the apparent oral clearance was about 4 times greater (Perucca & Richens 1979b). These findings following intravenous and oral administration of lidocaine are consistent wit h phenytoin having increased the hepatic intri nsic clearance and first-pass metabolism of lidocaine. a drug with a relatively high hepatic extraction ratio. At first sight. the interaction between phenytoi n and lidocaine may appear to be unimportant because lidocaine is nOt administered orally in the clinical uHCS 6. 41()..1:'1, 1965 Cunmngham JL. E'ans Do\l' llrona" D-glucanc ac,d ",creuun and acelan.lid,' pharmacol,neucs before and dUrlnl d'phcn. )lh)danIO,n adnunoslrllUon. EuroP In chron', alcoholics ClinICal PllarmacolOl' and TherapeuIlCs 30: 390397.1981 SandstD. Robln!>On JD. '»!~m RH .. I..... an RB \' un!, ( Effccl of I~,o"dallne on phcn"Oln ","rum con .. ~ntr:lI,on a relfO-

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sp«I"e [)rullnldll&C~ and (1,n,cal PharmloC) 11 267-272. 198 Sand)k R. Phcn)10ln 10..CII)' .nduced b)' mlctllcuon "Hh Ibu· profen. Soul h "fl"lcan Mrd,cal Joumal 62; 5'12. 1'182 53n!.Om LN . Be .. n Re. Sch~pcl GJ. Inl tr:lCUOn bc".een ph~n)· lo,n and valproatt MWl cal Journa l or AU~ltlllo~ 2 21t 1980 53unden MI . DI K he S. Anderson P. Rockhan] R Thc neurotoxIC'I) of m'!.Onlda~ok and liS relallonshlp 10 dOlot. half-life and COMentraUon ,n Ihe Strom Bnll~h Journal of Can~r )7 (Suppl 3) 268-270. 197' Sa"chu l RJ , RCCIOr TS. ForoJ,~ JJ. Lcpp.k IE Eff~';1 o(mnl,K"nta 'arnnauon on plasma phcn)loon conc ... ntr:ll1Qns TheraPl'Ulle Oru& Momtonnl I ~85-1'8. 19"\1 Schmldl D The ~1l«1 or pIlrn)IOOn and ethosu\lm,dc: on Jlnm· 'do .... metabolism ,n p.1l1enlS ,,"h ~Pllr~' Joomal of '(ur0101) 209 1l5·I~l I'P5 Sc"hm.dl D. t l hormOM bondln, sIobtJhn by plKn)loin . Ilnl"h Med,cal Journal 2; 9J4..935. 1971 V.uun NMA. FolK K"Id and Inloronvull.anl$. unoet I: 980.1963 WII~n- MD. Sinkc TA . Mlsontduok pmphcnl ncuroplllh)~ 115 Il'lnlonihlp 10 pluml collttnlnllon Ind OIMr dru8$. ClrKff Oln0ndrome TherapeuIK Drus Mon,lonn, 4 3S}'3S1. 1982 Ylltn GJ lnlCTKllon of phenylo,n and folK actd ; .n .hfm.lC upl;1onallon. Oln,cal Pharmac)"): 116. 1984 Ztchnsll JJ. llatdukew)'ch D. Dual dfo:ns of aJ"bam,uplnC"plKnyloin InlefICllon. Thcnpeullc Dru, MOllllonnl 9 21·23. 1987 Z.chnsko JJ. Ha,duktwych D. LeIKIa BJ. Carbamareplnc·phcny. lo,n ,nleraChon. Elcv'llon of plasma plKn)IOln COl\(cnlra\lon~ duc 10 carb.1omllep,ne comed,callon. Thcrapeullc Dru, Monl' tonn, 7; 51-S3. 1985

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AUlhors' addrm. Or ROf" L StJ/'(Nl. School of Pharmacy. Sollih AU\l.rahan InsmulC ofT«hl\Qloa). NDrlh T~. Alklaodt 5000. AUSlrll.a.