title: Systemic exposure of topical erythromycin in comparison to oral administration and the effect on cytochrome P450 3A4 activity.
abstract: OBJECTIVE
  Erythromycin is a macrolide antibiotic, which is frequently used as a topical formulation for the treatment of acne. It is also known as an inhibitor of the cytochrome P450 (CYP) isoenzyme 3A4. In this study, the systemic availability of topical erythromycin, hence the influence on the activity of CYP3A, is evaluated in comparison to orally administered erythromycin.
  
  
  METHODS
  Sixteen healthy volunteers received consecutively topical (two applications of 800 mg) and oral erythromycin (two dose groups, 250 and 1000 mg, with n = 8) to assess erythromycin pharmacokinetics. A microdose of midazolam (3 μg orally) was used to determine the effect on CYP3A activity.
  
  
  RESULTS
  After topical administration, erythromycin was detected in the plasma of every participant without causing a statistically significant alteration of CYP3A activity. After oral administration, the dose-normalized erythromycin exposure (AUC∞ ) was 1335 h ng ml(-1) after 250 mg and 3-fold higher after the 1000 mg dose (4051 h ng ml(-1); P < 0.01), suggesting nonlinear pharmacokinetics of erythromycin. Both oral doses inhibited CYP3A activity; midazolam clearance was decreased to 61% (250 mg) and 21% (1000 mg). The relationship between erythromycin exposure and CYP3A activity (Hill equation) revealed a 50% reduction of CYP3A activity by an erythromycin AUC∞ of 2106 h ng ml(-1).
  
  
  CONCLUSIONS
  Topical erythromycin did not cause clinically relevant CYP3A alterations, although low systemic availability of erythromycin was observed. This supports the assumption that treatment with topical erythromycin is not critical in terms of CYP3A inhibition. Furthermore, substantial nonlinearity of erythromycin pharmacokinetics after two different oral doses was observed, possibly due to autoinhibition.
authors.affiliation: Department of Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Carls
authors.forename: Julia
authors.initials: J
authors.lastname: Jedamzik
authors.forename: Lukas
authors.initials: L
authors.lastname: Witt
authors.forename: Nicolas
authors.initials: N
authors.lastname: Hohmann
authors.forename: Juergen
authors.initials: J
authors.lastname: Burhenne
authors.forename: Gerd
authors.initials: G
authors.lastname: Mikus
mesh_terms: D000284:Administration, Oral; D000287:Administration, Topical; D000328:Adult; D019540:Area Under Curve; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D004917:Erythromycin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D008297:Male
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004917:Erythromycin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: cytochrome P450 3A4; erythromycin; microdosing; midazolam; pharmacokinetics; topical