Absorption and bioavailability of oral erythromycin.

Abstract

1 Extent and rate of absorption of erythromycin were studied in 24 healthy volunteers whose disposition kinetics after i.v. injections had been previously documented. 2 Two clinically attractive oral dosage regimens were administered: erythromycin stearate tablets 1 h before meals (Regimen A), and erythromycin base capsules 30 min after start of meals (Regimen B), each equivalent to erythromycin 250 mg, 6 h apart for 9 doses. 3 Serum concentrations of erythromycin measured during the 1st and 9th (steady-state) dosing intervals resulted in higher maximum serum concentrations for Regimen A (median 1.1, range 0-3.3 and 2.7, 0.6-7.3 mg/l for Doses 1 and 9, respectively) compared with Regimen B (0.4, 0-2.2 and 1.4, 0.2-4.9 mg/l). 4 Absorption occurred earlier with Regimen A with times to maximum concentrations (median, range) being 128, 60-greater than 360 and 118, 75-210 min for doses 1 and 9 respectively, (lag times 75, 15- greater than 360 and 73, 10-110 min) compared with 303, 130-greater than 360 and 173, 45-greater than 360 min (lag times 183, 70-greater than 360 and 190, 20-330 min) for Regimen B. 5 Where it could be assessed, absolute bioavailability for Regimen A was approximately 30% (Dose 1) and 65% (Dose 9) and 40% for both doses of Regimen B. 6 Whereas individual serum concentration-time curves were accurately predicted by the mean for Regimen A, predictability for Regimen B was impossible due to prolonged and variable lag time. 7 The large intersubject variability in erythromycin serum concentration after oral administration, has been shown conclusively to be related to variability in absorption kinetics and absolute bioavailability rather than to variability in disposition kinetics.

Pharmacokinetic advantages of erythromycin estolate over ethylsuccinate as determined by high-pressure liquid chromatography

“…Large variability among subjects after oral absorption of erythromycin base preparations has been reported by several investigators (17,20,27). This study has also demonstrated substantial variability of the disposition of erythromycin esters (3,36,37).…”

“…The half-life of erythromycin base when administered as enteric-coating base has been reported between 1 and 2 h (7,22,27), but when erythromycin esters were administered as in this study, the half-life of erythromycin base varied between 1.54 and 5.83 h. In most cases, the apparent half-life of erythromycin base was close to that of erythromycin esters, suggesting that the elimination of erythromycin esters and hence the formation of erythromycin base were rate limiting (30).…”

Preclinical Pharmacokinetic Properties of the P-Glycoprotein Inhibitor GF120918A (HCl salt of GF120918, 9,10-Dihydro-5-methoxy-9-oxo-N-[4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]phenyl]-4-acridine-carboxamide) in the Mouse, Rat, Dog, and Monkey

“…Although a full dose-ranging study has not been performed with either GF120918A or ketoconazole in this monkey model, these results showing a similar order of magnitude effect with both a selective Pgp/BCRP inhibitor and a dual Pgp/CYP3A inhibitor suggest that in the monkey, Pgp/BCRP, rather than CYP3A, may be the primary factor limiting the absorption of erythromycin. Interestingly, erythromycin demonstrates substantially lower oral bioavailability in the monkey (ϳ2%; Girard et al, 1987;GlaxoSmithKline, unpublished data) than in humans (ϳ30 -65%; Mather et al, 1981). Although beyond the scope of this work, it would be intriguing to compare the in vitro permeability and transporter profile of erythromycin side by side in both human and nonhuman primate intestinal tissue, to ascertain whether differences in transporter activity may contribute to the observed species differences in pharmacokinetics.…”

Effects of cholinoceptor and 5‐hydroxytryptamine3 receptor antagonism on erythromycin‐induced canine intestinal motility disruption and emesis

“…These studies were prompted by numerous reports associating cramping, nausea, vomiting and diarrhoea with erythromycin treatment, which in some cases were severe enough to discontinue treatment (Shoemaker & Yow, 1954;Mather et al, 1981;Downey & Chaput de Saintonge, 1986;Hovi et al, 1987;Shanks et al, 1989). Erythromycin was found to have a disruptive effect on gastrointestinal motor patterns (Pilot et al, 1984;Itoh et al, 1984), even when administered at very low, subtherapeutic doses (Tomomasa et al, 1986;Otterson & Sarna, 1990).…”