Effects of gender and moderate smoking on the pharmacokinetics and effects of the CYP1A2 substrate tizanidine.
OBJECTIVE
We studied the effects of gender and smoking on the pharmacokinetics and effects of the cytochrome P450 (CYP) 1A2 substrate tizanidine.


METHODS
Seventy-one healthy young volunteers (male and female nonsmokers, male smokers) ingested 4 mg tizanidine. Plasma concentrations and pharmacodynamics of tizanidine were measured, and a caffeine test was performed.


RESULTS
Among nonsmokers, the peak concentration (C(max)) and area under concentration-time curve from 0 to infinity [AUC(0-infinity)] of tizanidine did not differ significantly between females and males. However, the half-life (t(1/2)) was 9% shorter in female nonsmokers than in male nonsmokers (P < 0.05). In male smokers, the t(1/2) was 10% shorter and the weight-adjusted AUC(0-infinity) 33% smaller than in male nonsmokers (P < 0.05). The caffeine/paraxanthine ratio was 35-40% smaller (P = 0.001) in male smokers than in nonsmoking males or females, but did not differ between males and females. Tizanidine lowered blood pressure and caused drowsiness significantly (P < 0.05) more in females than in either male groups. The effects on blood pressure were smallest in male smokers (P < 0.05).


CONCLUSIONS
Gender by itself seems to have no clinically significant effect on the pharmacokinetics of tizanidine, whereas smoking reduces plasma concentrations and effects of tizanidine. Any possible effect of gender and smoking is largely outweighed by individual variability in CYP1A2 activity due to genetic and environmental factors and in body weight. Careful dosing of tizanidine is warranted in small females, whereas male smokers can require higher than average doses.
Backman
Janne T
JT
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Schröder
Marika T
MT
Neuvonen
Pertti J
PJ
D000316:Adrenergic alpha-Agonists / Q000009:adverse effects / Q000493:pharmacokinetics*; D000328:Adult; D019540:Area Under Curve; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight; D002110:Caffeine / Q000493:pharmacokinetics; D003000:Clonidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D019388:Cytochrome P-450 CYP1A2 / Q000378:metabolism*; D004347:Drug Interactions; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D012737:Sex Factors; D012894:Sleep Stages / Q000187:drug effects; D012907:Smoking / Q000009:adverse effects*; D013806:Theophylline / Q000493:pharmacokinetics
D000316:Adrenergic alpha-Agonists; D002110:Caffeine; C023754:tizanidine; D013806:Theophylline; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2; D003000:Clonidine; C021183:1,7-dimethylxanthine