C L I N I C A L P H A R M A C O L O G Y & T H E R A P E U T I C S

1 4 4 American Society for Clinical Pharmacology and Therapeutics FEBRUARY 1999

PI-107 META-CHLORO-PHENYLPIPERAZINE (mCPP): P450-3A-

DEPENDENT FORMATION FROM NEFAZODONE AND TRAZODONE; P450-2D6-DEPENDENT CLEARANCE. L.L. yon Moltke,* A. Zalma,* B.W. Granda,* J.M. Grassi,* R.I. Shader, and D.J. Greenblatt, Tufts University, Boston, MA.

mCPP is a pharmacologically active metabolite of both nefa- zodone (NEF) and trazodone (TRAZ). In vitro studies using human cytochromes from cDNA-transfected human lymphoblas- toid cells showed that mCPP formation from NEF or TRAZ was nearly completely mediated by P450-3A4. In liver microsomes, formation of mCPP from NEF (Km=21 ~tM; Vmax/Km=0.19 ml/mirdmg protein) or from TRAZ (Km=185 ~tM; Vmax/Km=0.06) was strongly inhibited by ketoconazole. How- ever, formation of para-OH-mCPP from mCPP in vitro was mediated solely by heterologously-expressed P450-2D6, consis- tent with a Michaelis-Menten (M-M) pattern having high affin- ity (Kin=2.7 ktM). In liver microsomes, p-OH-mCPP formation was consistent with the sum of two M-M reactions, with 96% of net intrinsic clearance (0.54 ml/mirdmg protein) attributable to the high-affinity component (Km=l.8 ~M). At 10 ktM mCPP, for- marion of p-OH-mCPP was strongly inhibitable by quinidine (IC50=0.16 ~tM); this is smaller than the ICs0 of 0.55 ~M for quinidine inhibition of dextrorphan production from 25 IxM dex- tromethorphan. Dependence of mCPP clearance on P450-2D6 explains clinical findings of elevated mCPP levels in 2D6 "poor metabolizers," and in patients coadministered fluoxetine. Vmax/K m for production of mCPP from NEF or TRAZ is smaller than Vmax/K m for transformation of mCPP itself, thereby explain- ing the relatively low steady-state levels of mCPP in patients receiving NEF or TRAZ.

PI-109 AZITHROMYCIN-THEOPHYLLINE INHIBITION-INDUC-

TION INTERACTION. ET. Pollak. MD, PhD, D.M. MacNeil, MD,* Dept of Medicine, Dalhousie University, Halifax, Canada.

Azithromycin (AZ) is a macrolide purported to have no pharma- cokinetic interaction with methylxanthines. A reproducible drop in peak serum tbeophylline concentrations (THEO) was seen in a 68- yo man 5 days after stopping AZ. We studied late interaction of AZ with controlled release theophylline 200 mg BID (Theodur~) given for 3 weeks to a pilot subject and a group of 4 healthy males, 27-36 yo. THEO was mea- A

..I sured at before, during ~ 10 and after 5 days of AZ ~* 8 (500 mg Day 1 + 250 mg daily Days 2-5). _~ 6 Pilot and mean THEO "~ 4 are plotted. At Day 10 (5 ~ 2 days post AZ) THEO o ~ ," 0 declined rapidly in every t~ subject (p=0.001). The drop occurs just under

�9 Pilot

Mean of 4 Subj

I . . . . I " " I " " I

0 3 6 9 12 15 Time (days)

two half-lives (2 • 68 h) post last AZ dose, when [AZ] falls to less than 30% of values after last dose. Changes in THEO after AZ are small in magnitude and not likely of clinical significance unless sam- pies are measured during the transient drop which might lead to inap- propriate increase in dosage. Mild elevation of THEO while [AZ] is therapeutic, followed by reproducible depression of THEO suggests an inhibition by reversible binding of AZ to cytochrome P450 bal- anced by a concomitant induction of P450 enzymes. THEO then drops when inhibiting [AZ] declines 5 days after AZ withdrawal, leaving a greater than normal number of P450 sites exposed.

PI-108 ASSESSMENT OF BIOEQUIVALENCE OF INHALED

PRODUCTS VIA IN-VWO DEPOSITION DATA. K.E Roonev. PhD, S.P. Newman, PhD, and I.R. Wilding, PhD, Pharmaceutical Profiles, Highfields Science Park, Nottingham, NG7 2QP, UK.

With traditional oral products, bioequivalence is demonstrated by a comparison of confidence intervals for certain pharmacoki- netic parameters e.g. AUC & Cmax. With drugs given by the pul- monary route, therapeutic effect does not depend upon systemic drug levels - - the drugs themselves act locally. Consequently, traditional bioequivalence studies are inappropriate. Utilizing the in-vivo imaging technique of gamma scintigraphy, it is possible to show that two inhalers or formulations containing the same amount of the same drug can give the same whole and regional lung deposition i.e. it is possible to quantifiably demonstrate that the same amount of drug is delivered to the same areas of the lungs for two different products. It is therefore logical that the two products will be therapeutically equivalent - - gamma scintigraphy can thus be seen as a fully validated surrogate for clinical efficacy.

PI-110

[~2-ADRENERGIC RECEPTOR ([~2AR) POLYMORPHISM AFFECTS ALBUTEROL CONCENTRATION (Cp)-RESPONSE RELATIONSHIP IN ASTHMATICS. J.A. Johnson, PharmD, D.B. Thomason, PhD,* M.H.N. Mohamed, PharmD,* T.H. Self, PharmD,* L.V. Eberle, MD,* J.J. Lima, PharmD, Univ of Tennessee Colleges of Pharmacy and Medicine, Memphis, "IN.

Purpose: To determine if common polymorphisms of the ~2AR (Arg16---)Gly16 & G1n27-~Glu27) affect the albuterol Cp- response relationship. Sixteen moderate asthmatics who with- held inhaled steroids for 24h and ~-agonist for 36h received oral albuterol 8 rag. [~2AR genotype was determined by allele specific oligonucleotide hybridization, albuterol Cp by HPLC and FEV 1 by spirometry. The median (range) area under the response (%AFEV1)-C p curve (AURC0.12) was greater in Argl6 homozy- gores (hmz) than in patients possessing Gly at codon 16 (Gly 16 hmz + heterozygotes (htz)) (194 (45 to 237) %*ml/ng vs 30 (-337 to 146) %*ml/ng, respectively, p<0.05). AURC0.1~ was similar in Gly16 hmz and htz. Slopes describing rise to peak response were also different based on genotype (Argl6 hmz! 1.42 %*ml/ng vs Glyl6 hmz+htz: 0.55 %*ml/ng, p<0.05). The codon 27 polymorphism had no effect on the albuterol Cp-response rela- tionship. Conclusions: Asthmatics who are Arg16 hmz have a greater response to [~2-agonist therapy than asthmatics possess- ing Gly at codon 16.