Drug Invest. 6 (3): 176-179, 1993 01 I 4-2402/93/0003-01 76j$02.00/0 © Adis International Limited. All rights reserved.

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Paracetamol Pharmacokinetics in Pregnancy Louise Beaulac-Baillargeon and Sylvain Rocheleau Centre de Recherche H6pital St-Fran~is d'Assise, Ecole de Pharrnacie, Universite Laval, Quebec, Canada

Because no evidence of teratogenicity has been demonstrated and no untoward clinical effects have been reported with paracetamol, it is the most common analgesic/antipyretic agent used during pregnancy. Paracetamol is rapidly absorbed and has a half-life of around 2 hours (Clissold 1986; Dou­gall et al. 1983; Nimmo & Prescott 1978). Serum concentrations between 10 and 20 mg/L are gen­erally considered to be therapeutically effective, while > 150 mg/L may produce hepatic necrosis and > 400 mg/L is considered to be toxic. A lethal concentration is around 1500 mg/L (Winek 1976).

Physiological changes during pregnancy can modify the absorption, metabolism and excretion of many drugs (Beaulac-Baillargeon 1990; Krauer et al. 1980). Studies have been carried out to in­vestigate the influence of pregnancy on paraceta­mol absorption and elimination. Simpson et al. (1988) reported that gastric emptying is delayed after 12 weeks of pregnancy. Rayburn et al. (1986) reported that the absorption and disposition of paracetamol are not affected by pregnancy. Miners et al. (1986) reported a 58% increase in clearance due to an increase in the glucuronidation and ox­idation processes by the 31 st week of pregnancy.

This paper presents the pharmacokinetics of paracetamol in a case-controlled female. Analysis was carried out before the patient became pregnant and during the 12th, 20th and 30th weeks of preg­nancy. This case provides an insight into the preg­nancy-induced modifications of paracetamol phar­macokinetics, which will assist in ascertaining when

these changes become important, and when dosage adjustments are necessary.

Case History

A 23-year-old female Canadian laboratory worker participated in this study. The protocol was approved by the Hospital Ethics Committee. The subject was well informed and gave written con­sent prior to each treatment phase. During preg­nancy, she was allowed to continue with the study only after obstetrician authorisation at each stage.

She became pregnant 1 month after beginning the study. Her body mass index (BMI) was 22 kg/m2 prior to pregnancy, and increased to 27 kg/m2 by the 30th week. She was a nonsmoker and in good health except for experiencing headaches, for which she was prescribed paracetamol. She took no other medication that could interfere with the metabolism of paracetamol.

Prior to dosage administration, the patient fasted for 3 hours. With the patient in a semirecumbent position, a dose of paracetamol 650mg (Tylenol@) was given with 200ml of tap water at 1O.00am. Blood specimens were taken before and at 10, 20, 30, 40 and 50 minutes and 1, 1.5, 2, 2.5, 3, 3.5 and 4 hours following drug administration. Plasma was separated by centrifugation and frozen at - 20·C until assayed. Haematocrit values were 41, 39, 37 and 35% at 0, 12, 20 and 30 weeks, respectively.

Serum paracetamol was measured in triplicate by high pressure liquid chromatography (HPLC) using an LKB Ultrapac spherisorb ODS-2, 3"m (4.6

Paracetamol Pharmacokinetics in Pregnancy

x loomm) column and LKB Lichrosorb RP8, 3~m (4 X 100mm) precolumn. The mobile phase con­tained methanol: water (20 : 80) and was delivered at a flow rate of 0.8 ml/min. Column effluent was measured at 254nm.

A l-compartment model was used for this ex­periment and the serum concentrations of para­cetamol were assumed to decline monoexponen­tially. Peak serum concentrations were defined by Cmax at the corresponding sampling time (tmax).

Cmax and tmax were evaluated graphically. Areas under curves were calculated by the trapezoidal rule, with extrapolation to infinity (AVCO-oo). The elimination half-life (t'l2) was determined by least­square regression analysis from the slope of the log concentration versus time curve. The apparent oral clearance of paracetamol was calculated by the equation:

CL = F· Dose/AVC

where F (biodisponibility) was considered to be 88% (Forrest et al. 1982). The dose required to maintain a 10 mg/L concentration (C) was calculated as:

Dose = C· kel • t • V d (L/kg) • kg· 1000ml/F

where kel is the elimination rate constant (Bessner 1990). Experimental values were used to calculate doses for each week of pregnancy.

177

Results

Table I compares the pharmacokinetic values obtained after the oral administration of paracet­amol 650mg. Prepregnant values were compared with pregnant values obtained from the same woman.

Comparisons of plasma paracetamol concentra­tions between each week studied are shown in fig­ure I. The tmax remained constant for each week of pregnancy studied. Compared with the control, peak serum concentrations diminished signifi­cantly during pregnancy from the control value of 12.91 mg/kg. A decrease of 45, 62 and 60% was observed during the 12th, 20th and 30th weeks, re­spectively, with the corresponding AVCs being much lower than the control AVe. A decrease of 49, 42 and 55% was calculated for weeks 12, 20 and 30, respectively. This indicates that the effect was near maximal by the 12th week of pregnancy, the earliest week studied.

A similar change was observed with the appar­ent volume of distribution (V d). A volume of 60.77L (0.84 L/kg) was calculated before preg­nancy, increasing to 100, 90 and 105L (1.35, 1.16, 1.19 L/kg) during the 12th, 20th and 30th weeks, respectively. Compared with nonpregnant values, oral clearances and elimination constants were

Table I. Mean pharmacokinetic values following the oral administration of paracatamol 650mg in a 24-year-old female

Characteristics Week

0 12 20 30

Age (y) 23 24 24 24 Weight (kg) 72 74.5 78.5 88.5 8MI (kg/m2) 22.15 22.96 24.15 27.23 Cmax (mg/L) 12.91 7.07 4.83 5.28 tmax (min) 30 30 35 30 Vd (L) 60.77 100.81 90.73 105.28 Vd (L/kg) 0.64 1.35 1.16 1.19 kel (h-1) 0.37 0.437 0.435 0.487 t'f.! (h) 1.64 1.58 1.59 1.42 CL (L/h) 22.79 44.05 39.54 51.38 CL (ml/min/kg) 5.25 9.83 8.42 9.67

AUC (mg/min/L) 1506 779 868 668

Abbreviations: 8MI = body mass index; Cmax .. peak serum concentration; tmax .. time to Cmax; Vd .. volume of distribution; kel .. elimination rate constant; t'f.! = elimination half-life; CL = oral clearance; AUC = area under the serum concentration-time curve.

178

20

(5::J" 15 EO, ~E. o c:

m~ 10 0..1:; E c: 2 ~ ~ 8 5

9, :0. i ~~

"0 ••• .~ 0---0---0-

~ ---0---

O~~~~~-r~'-~~~~-r~, o 30 60 90 120 150 180 210 240

Time (min)

Fig. 1. Serum paracetamol concentrations versus time fol­lowing a single oral administration of paracetamo\ 650mg before pregnancy (0) and during the 12th (e), 20th (0) and 30th (_) weeks of pregnancy.

clearly increased by the 12th week. Half-lives were consequently 15 to 23% lower than control data.

Discussion

All control pharmacokinetic data determined before pregnancy were in close agreement with those reported in the literature (Miners et al. 1983). Results presented here indicate that pregnancy-in­duced kinetic changes are meaningful by the 12th week, and may have taken place even earlier.

Weight gain during pregnancy is partly due to an increase in plasma volume and extracellular water. An increase in total body water is observed at the beginning of pregnancy and reaches maximal values by the 20th week. Paracetamol is distributed in total body water, which may explain why the lowest Cmax achieved was observed at the 20th week.

Paracetamol depends almost entirely upon the hepatic route for elimination (Clissold 1986). Min­ers et al. (1986) reported that between the 31 st and 38th weeks of pregnancy, glucuronidation and ox­idation processes were enhanced by 75 and 85%, respectively. Our results support such findings and suggest that the metabolic induction begins much earlier than the 31 st week since the CL and ke1 are already lowered by the 12th week. When compared with the control value, AUC was reduced by 50%

Drug Invest. 6 (3) 1993

by the 12th week, and this rate was maintained until the end of pregnancy. A possible mechanism to explain these results requires the measurement of further variables such as glucuronide and sul­phate metabolites and plasma volume expansion and is, thus, beyond the scope of this experiment.

Therapeutic Implications

It is of interest to note how efficacy correlates with serum concentrations during pregnancy. To our knowledge, none of the drugs that are known to have modified pharmacokinetics have been evaluated to demonstrate if this corresponds with a change in effect. Thus, more studies are required, particularly with paracetamol, to demonstrate the clinical relevance of such findings.

In selecting a dosage for a patient, the usual ap­proach is to base the choice on average population values, except for paediatric and geriatric patients. However, recent studies have demonstrated the need for a different therapeutic approach during pregnancy. This case report suggests that the para­cetamol dose should be increased or the dosage in­terval shortened after the 12th week of pregnancy.

Table II shows the adjustment to the regimen that is required for a given week of pregnancy if, firstly, the interval between dosages is kept con­stant and, secondly, if the dosage is kept constant. The values obtained indicate the need to alter the regimen not only during pregnancy, but also in nonpregnant women. Our results confirm that a dose of at least Ig is required in a 'nonpregnant' patient to achieve a therapeutic serum concentra­tion. During pregnancy, up to 2g paracetamol may be required to reach a serum concentration of 10 mgjL if a 4-hourly interval between administra­tions is maintained. The maximum recommended dose of 4 gjday is reached after 2 administrations. The potential risk of toxicity should, however, be fully evaluated. High doses of paracetamol form a highly reactive intermediate that reacts with sulfhydryl groups in proteins and with glutathione. When hepatic glutathione is depleted, the reaction with hepatic protein is increased and hepatic ne­crosis is the result. Therefore, drugs or pathological

Paracetamol Pharmacokinetics in Pregnancy 179

Table II. Dosage adjustment required for paracetamol during pregnancy (calculated from data collected from a 24-year-old female)

Week

0

Dose given mg 650 mg/kg 9.03

12

650 8.73

20

650 8.28

30

650 7.34

Modifications required to achieve a serum concentration of 10 mg/l Intervals between doses (h) or 2.47 1.29 1.45

1797 1.11 2335 Calculated dose (mg) 1052 2010

conditions inducing the oxidative pathway may in­crease the utilisation of glutathione, reducing glu­tathione stores and increasing the risk. Since the oxidative pathway is reported to be increased dur­ing pregnancy (Miners et al. 1986), pregnancy may bring an additional risk for high dose administra­tion, at least in patients reported to have enhanced susceptibility. Hepatic necrosis is unlikely with serum concentrations lower than 120 mg/L, except in the presence of alcohol abuse, previous hepatic disease, or malnutrition that may bring low glu­tathione reserves, or for those who are taking drugs that induce liver oxidative processes because of the higher utilisation of glutathione stores (Black 1984; Meredith & Goulding 1980; Zimmerman 1981). The study presented here highlights a number of important problems associated with the safety of paracetamol and its capacity to deliver sustained analgesic concentrations. During pregnancy, sug­gested doses may be toxic to the metabolic pro­cesses of the mother and/or her fetus. Therefore, should paracetamol only be prescribed during pregnancy for minor ailments where less than 4g per day is required? From the above data, it ap­pears that additional studies are urgently required to define the appropriate dosage and to evaluate serum concentrations versus clinical efficacy.

Acknowledgement

We are grateful for the technical assistance of Marie Belanger for blood sample collections, and thank the Re­search Centre of Saint-Fran~ois d'Assise Hospital for

clinical facilities and Gilles Allard for his assistance in the preparation of the manuscript.

References

Bessner JG. Variations des concentrations en fonction du mode d'admin­istration. In Aiache et al. (Eds) Traite de pharmacocinetique, 2nd ed., pp. 219-237, Ed Vigot, Paris, France, and PUM, Montreal, Canada, 1990

Black M. Acetaminophen hepatotoxicity. Annual Reviews of Medicine 35: 577-593, 1984

Beaulac-Baillargeon L. Pharmacocinetique pendant Ia grossese et la lacta­tion. In Aiache et al. (Eds) Traite de biopharmacie et pharmacocinetique, 2nd ed., pp. 331-343, Les presses de l'Universire de Montreal, Montreal, 1990

Clissold SP. Paracetamol and phenacetin. Drugs 32 (Suppl. 4): 46-59, 1986 Dougall JR, Cunningham B, Nimmo WS. Paracetamol absorption from Par­

amax, Panadol and Solpadeine. British Journal of Clinical Pharmacology 15: 487-489, 1983

Forrest JAH, Clements JA, Prescott LF. Clinical pharmacokinetics of para­cetamol. Clinical Pharmacokinetics 7: 93-107, 1982

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Meredith TJ, Goulding R. Paracetamol. Postgraduate Medical Journal 56: 459-473, 1980

Miners JO, Atwood J, Birkett DJ. Influence of sex and oral contraceptive steroids on paracetamol metabolism. British Journal of Clinical Pharma­cology 16: 503-509, 1983

Miners JO, Robson A, Birkett DJ. Paracetamol metabolism in pregnancy. British Journal of Clinical Pharmacology 55: 1353-1356, 1986

Nimmo WS, Prescott LF. The influence of posture in paracetamol absorp­tion. British Journal of Clinical Pharmacology 5: 348-349, 1978

Rayburn W, Shukla U, Stetson P, Piehl E. Acetaminophen pharmacokin­etics: comparison between pregnant and non pregnant women. American Journal of Obstetrics and Gynecology 155: 1353-1356, 1986

Simpson KH, Stakes AF, Miller M. Pregnancy delays paracetamol absorp­tion and gastric emptying in patients undergoing surgery. British Journal of Anaesthesia 60: 24-27, 1988

Winek CL. Tabulation of therapeutic, toxic, and lethal concentrations of drugs and chemicals in blood. Clinical Chemistry 22: 832-836, 1976

Zimmerman HJ. Effects of aspirin and acetaminophen on the liver. Archives of Internal Medicine 141: 333-342, 1981

Correspondence and reprints: Dr Louise Beaulac-Baillargeon, Ecole de Pharmacie, Universite Laval, Ste-Foy, Quebec, Canada, GlK 7P4.