Further studies on the pharmacokinetics of perhexiline maleate in humans

Abstract

We have performed single-dose pharmacokinetic studies on perhexiline in eight young volunteers, each given 300 mg of Pexid orally, using an h.p.l.c. method for the separation and quantification of the drug and its monohydroxy metabolites in plasma and urine. The plasma concentration of the cis-monohydroxyperhexiline (peak of 473 +/- 43 ng/ml at 7.5 +/- 2.0 h) was always higher than for unchanged perhexiline (peak of 112 +/- 20 ng/ml at 6.5 +/- 2.0 h) whereas the concentration of the transmetabolite was either low or undetectable in plasma. These findings indicate the occurrence of stereospecific pre-systemic metabolism of perhexiline which reduces the bioavailability of the parent drug. The plasma elimination half-life of perhexiline was 12.4 +/- 6.1 h (range 7-23 h) while that for cis-monohydroxyperhexiline was 19.9 +/- 7.7 h (range 10-29 h). Not more than 0.3% of unchanged perhexiline was excreted in the urine over five days in eight subjects. Between 3 and 23% of the orally administered drug was excreted as the cis- or trans-monohydroxy metabolites, the ratio of trans to cis metabolites being 0.52 +/- 0.20.

Studies on the metabolism of perhexiline in man

“…These second peaks are of the same order or larger than the primary peaks observed at about 3-5 h after dosage. Biphasic plasma elimination time curves are observed for other compounds [16,17] and it is observed in Table 1 of Amoah et al [18] that there is a suggestion of secondary peaks in 12 out of 16 plasma perhexiline or M1 elimination profiles. This phenomenon offers alternatives to extensive tissue binding as an explanation for the very slow elimination of a single dose of perhexiline in man.…”

Effect of CYP2D6 metabolizer status on the disposition of the (+) and (−) enantiomers of perhexiline in patients with myocardial ischaemia

“…As we have demonstrated that the plasma protein binding of perhexiline is not enantioselective, such processes may include other CYP isoforms involved in the metabolism of perhexiline, or transporters involved in its absorption, renal, biliary or intestinal excretion. In extensive metabolizers, renal clearance accounts for less than 1% of total perhexiline clearance [16,24]. Although renal clearance will be a greater proportion of total perhexiline clearance in poor metabolizers, it is unlikely to account for more than 10%, suggesting that enantioselectivity of perhexiline's apparent oral clearance in poor metabolizers is unlikely to be due to enantioselectivity in its renal clearance.…”

“…Nevertheless, such studies have demonstrated that rac-perhexiline is cleared primarily by hydroxylation at the fourth carbon of the cyclohexyl moieties ( Fig. 1), forming monohydroxy metabolites in the cis-OH and trans-OH-configurations, also referred to as M1 and M3, respectively [16,17]. Formation of the cis, but not the trans, metabolites from racperhexiline is considered to be catalysed almost exclusively by CYP2D6 [18] with a K m value within the range of total plasma perhexiline concentrations attained clinically [19].…”

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

“…However, it has been reported that in a small group of volunteers receiving 400 mg of perhexiline daily for 14 days, 24 h recoveries of unchanged perhexiline in faeces on days 12, 13 or 14 averaged 7.7% (range 0–32.5%), suggesting good absorption from the gastrointestinal tract [11]. The major determinant of perhexiline clearance appears to be hepatic metabolism, since in humans only approximately 0.1% of a dose is eliminated as unchanged drug in urine [12]. Perhexiline forms two primary monohydroxy (OH) metabolites, cis ‐OH‐perhexiline and trans ‐OH‐perhexiline, which can undergo further secondary metabolism to dihydroxy metabolites, as well as glucuronide conjugates [11].…”