The metabolism and kinetics of doxazosin in man, mouse, rat and dog.

Abstract

1 The metabolic fate of doxazosin was investigated in man, mouse, rat and dog using 14C-labelled compound. Bioavailability and pharmacokinetic studies were also conducted with nonlabelled drug, using a specific h.p.l.c. method. 2 Following both oral and intravenous administration, the major route of elimination of drugrelated compounds was via the faeces for all species studied. Comparison of the oral and intravenous data show that doxazosin is completely absorbed in man, mouse and rat and is moderately well absorbed in dog. 3 The drug is extensively metabolized, e.g. only about 5 % of the dose was excreted unchanged in man. Metabolism in man mainly involves 6-and 7-O-demethylation and 6' and 7'-hydroxylation. These and some minor products were common to the mouse, rat or dog and man.4 Plasma protein binding was high in all species studied, ranging from 95.3 % in the rat to 98.3 % in human patients. 5 Oral bioavailability is 60% in dog and approximately 50% in the rat, which is similar to the value of 63 % reported for man at therapeutic doses. Mean plasma clearance values were 13 ml min-' kg-' (dogs), 30 ml min-' kg-' (rats) and 1.2 ml min-' kg-' (human subjects). Mean plasma half-life values were 5 h in dogs and 1.2 h in rats: a value of 9 h was reported for human volunteers (cf. 2.5 h for prazosin). The long plasma half-life of doxazosin provides the basis for once-daily dosing.

Orally applied doxazosin disturbed testosterone homeostasis and changed the transcriptional profile of steroidogenic machinery, cAMP/cGMP signalling and adrenergic receptors in Leydig cells of adult rats

“…The mean plasma clearance values for rats were 30 mL/min/kg BW, whereas those for human subjects were 1.2 mL/min/kg. The mean plasma half-life values were 1.2 h in rats, while the value of 9 h was reported for human volunteers (Kaye et al, 1986). Doxa oral bioavailability in the rat is approximately 50%, which is similar to the value of 63% reported for man at therapeutic doses.…”

“…To mimic the most likely route of human exposure to selective a1-ADRs blockers, rats were subjected to po-administration of Doxa in clinically relevant dose (5 mg/kg BW) described before (Kaye et al, 1986), for once (19Doxa), or for two (29Doxa) orDoxazosin po-application impaired levels of circulating LH/ testosterone and disturbed androgens homeostasis in testis Po-application of Doxa, widely used selective a1-ADRs blocker, for once, or two or 10 consecutive days caused significant decrease in the level of LH ( Fig. 2A) and androgens ( Fig.…”

“…To mimic the most likely route of human exposure, rats were subjected to oral administration (po) of Doxa in clinically relevant dose for rat model (5 mg/kg BW) described before (Kaye et al, 1986). It is important to point out that the clinically relevant doses for humans stated in treatment guidelines are in the initial dosage of Doxa mesylate 1 mg once daily, and this is titrated to a maximum of 8 mg for BPH or 16 mg for hypertension.…”

“…Doxa oral bioavailability in the rat is approximately 50%, which is similar to the value of 63% reported for man at therapeutic doses. The long plasma half-life of Doxa provides the basis for once-daily dosing (Kaye et al, 1986). Groups of rats (six of rats in each) were left undisturbed (Control) or treated po with either water or Doxa once (19Doxa), or for two (29Doxa) or 10 (109Doxa) consecutive days.…”

“…Accordingly, this study was designed to systematically evaluate the effect of Doxa po-application in clinically relevant dose (Kaye et al, 1986) on: the steroidogenic machinery homeostasis, cAMP/cGMP signalling and transcriptional profile of all ADRs in Leydig cells. The study followed the following: (i) The levels of circulating LH and androgens (T+DHT); (ii) The androgens levels in testicular interstitial fluid (TIF), extracted from testes and produced by testes in basal/ hCG-stimulated environment; (iii) Ex vivo steroidogenic activity/ capacity Leydig cells; (iv) The expression of transcripts for steroidogenic machinery elements ( Fig.…”