Pregnancy and use of oral contraceptives reduces the biotransformation of proguanil to cycloguanil

Eur J Clin Pharmacol. 2003 Oct;59(7):553-7. doi: 10.1007/s00228-003-0651-x. Epub 2003 Aug 30.


Objective: To determine the effects of late pregnancy and also oestrogen supplementation on the CYP2C19-mediated biotransformation of proguanil (PG) to its active antifol triazine metabolite cycloguanil (CG).

Methods: Case control study conducted on the NW border of Thailand; a single dose of PG (4 mg/kg) was administered to Karen women in late pregnancy and a single blood and urine sample taken 6 h later. Women were studied in late pregnancy (>36 weeks) and restudied 2 months after delivery. A separate cohort of Karen women newly attending a birth-control clinic were studied before and 3 weeks into their first course of oral contraceptives (OCP: levonorgestrel 0.15 mg and ethinyloestradiol 0.03 mg). Forty-five pregnant women and forty-two healthy OCP users were studied.

Results: The results were similar in both groups; pregnancy and OCP use were both associated with reduced formation of cycloguanil (CG). Impaired PG biotransformation was seen in women with the "extensive metaboliser" phenotype (urine PG/CG ratio <10). CG levels, adjusted for dose, were a median (range) 73% (-59 to 420%) higher following the pregnancy than during the pregnancy in women characterised as extensive metabolisers ( P<0.001). CG levels in women characterised as extensive metabolisers were 34% (-54 to 323%) higher before than while taking the OCP ( P<0.01).

Conclusion: Late pregnancy and OCP use impair biotransformation of the active antimalarial metabolite CG from the parent PG. This may be mediated by oestrogen inhibition of CYP2C19 activity. The dose of PG should be increased by 50% in these groups.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimalarials / blood
  • Antimalarials / pharmacokinetics*
  • Antimalarials / urine
  • Biotransformation / drug effects
  • Case-Control Studies
  • Cohort Studies
  • Contraceptives, Oral, Hormonal / pharmacology*
  • Female
  • Humans
  • Malaria, Falciparum / prevention & control
  • Pregnancy / blood
  • Pregnancy / metabolism*
  • Pregnancy / urine
  • Pregnancy Complications, Parasitic / prevention & control
  • Pregnancy Trimester, Third
  • Proguanil / blood
  • Proguanil / pharmacokinetics*
  • Proguanil / urine
  • Thailand
  • Triazines / blood
  • Triazines / metabolism*
  • Triazines / urine


  • Antimalarials
  • Contraceptives, Oral, Hormonal
  • Triazines
  • cycloguanil
  • Proguanil