Therapeutic Monitoring of the Anti-Anginal Drug Perhexiline Maleate

Abstract

Patients taking oral doses of perhexiline maleate have been examined. Measurement of serum perhexiline concentrations established that different dose requirements between patients were necessary due to the different doses at which drug saturation was achieved. Measurement of serum perhexiline concentrations are essential if side-effects from the drug are to be avoided.

Determination of the 4-monohydroxy metabolites of perhexiline in human plasma, urine and liver microsomes by liquid chromatography

“…dose recovery of 9.4 ± 5.1 and 1.8 ± 1.1%, respectively (Table 5). This finding is in contrast to other research that found cis-OH-PHX in greater concentrations in urine [7,[15][16][17][18], although all of these studies except one [7] used single doses of PHX that may have minimised the saturation of CYP2D6-mediated cis-monohydroxylation observed with repeated PHX dosing [23]. Free and glucuronidated cis-OH-PHX accounted for a mean (±S.D.)…”

CYP2B6, CYP2D6, and CYP3A4 Catalyze the Primary Oxidative Metabolism of Perhexiline Enantiomers by Human Liver Microsomes

“…An investigation of the in vitro enzyme kinetics of PHX 4-monohydroxylation in human liver microsomes (HLMs) determined that it is almost exclusively catalyzed with high affinity by CYP2D6 in EMs, with K m values within the range of therapeutic PHX concentrations in plasma (Sørensen et al, 2003); this is consistent with the nonlinear kinetics observed clinically in EMs (Cooper et al, 1985). The intrinsic clearance of PHX was approximately 100-fold lower in PMs, presumably mediated by P450 isoforms other than CYP2D6 with a much lower affinity for PHX (Sørensen et al, 2003), although these iso-forms and the 4-monohydroxy metabolites they produced were not identified.…”

Pharmacokinetics of the antianginal agent perhexiline: relationship between metabolic ratio and steady‐state dose

“…Although clearly effective as an antianginal agent, clinical use of perhexiline has been limited by its narrow therapeutic index and large inter-and intraindividual variability in pharmacokinetics. A number of early studies of perhexiline metabolism have suggested that this variability is due primarily to saturability and genetic polymorphism in CYP2D6-catalysed formation of cis-OH-perhexiline [13,15,16,18]. Indeed, the significant linear correlation observed between C OHPx;ss /C Px;ss and CL Px /F in the first retrospective study (Figure 3a) supports the formation of cis-OH-metabolite as the primary determinant of perhexiline clearance, and additionally suggests that there was relatively little interindividual variability in the clearance of cis-OH-perhexiline.…”