To the Editor:-We read with interest the recent study by Birmingham et al. [1]concerning the pharmacokinetics of rectal acetaminophen in children. The estimate for clearance (CL/F) of 5.46 ml [center dot] kg sup -1 [center dot] min sup -1 is similar to that previously reported in children after rectal administration. [2]However, the volume of distribution (Vd/F) estimate of 385 ml/kg seems to be low. The relative bioavailability (F) of rectal compared with oral acetaminophen formulations has been reported as 0.52 (range, 0.24–0.98)[5]and even as low as 0.3. [6]Estimates [3,4]of acetaminophen's Vd/F in children are within the range of 700–1,000 ml/kg after oral administration. We would therefore expect Birmingham et al. [1]to have found a Vd/F of at least 1,400–2,000 ml/kg, which is similar to the value of 1,903 ml/kg previously reported after rectal administration. [2],Figure 1shows the “average” profile observed by Birmingham et al. [1](20 mg/kg), and predictions made using their dissolution time model with a Vd/F of 385 ml/kg compared with a Vd/F of 1,400 or 2,000 ml/kg assuming rapid dissolution. The “average” concentrations illustrated [1]after 20 mg/kg peak around 5–6 micro gram/ml, not 8–10 micro gram/ml predicted by Birmingham et al.'s [1]model. However, when Vd/F in the range of 1,400–2,000 ml/kg is used, the model approximates more closely the reported “average” concentrations. It is clear that Birmingham et al.'s [1]model does not match their own observed values.

Figure 1. Time-concentration profiles after administration of 20 mg/kg rectal acetaminophen. Parameters [1]used were CL/F, 5.46 ml [center dot] kg sup -1 [center dot] min sup -1; Ka, 0.00468 min sup -1; Vd/F and zero order dissolution times (DT) as shown. The simulations using Vd/F of 1,400 or 2,000 ml/kg assumed rapid dissolution.
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Figure 1. Time-concentration profiles after administration of 20 mg/kg rectal acetaminophen. Parameters [1]used were CL/F, 5.46 ml [center dot] kg sup -1 [center dot] min sup -1; Ka, 0.00468 min sup -1; Vd/F and zero order dissolution times (DT) as shown. The simulations using Vd/F of 1,400 or 2,000 ml/kg assumed rapid dissolution.

Figure 1. Time-concentration profiles after administration of 20 mg/kg rectal acetaminophen. Parameters [1]used were CL/F, 5.46 ml [center dot] kg sup -1 [center dot] min sup -1; Ka, 0.00468 min sup -1; Vd/F and zero order dissolution times (DT) as shown. The simulations using Vd/F of 1,400 or 2,000 ml/kg assumed rapid dissolution.
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Figure 1. Time-concentration profiles after administration of 20 mg/kg rectal acetaminophen. Parameters [1]used were CL/F, 5.46 ml [center dot] kg sup -1 [center dot] min sup -1; Ka, 0.00468 min sup -1; Vd/F and zero order dissolution times (DT) as shown. The simulations using Vd/F of 1,400 or 2,000 ml/kg assumed rapid dissolution.

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Finally, we agree that suppository size may affect absorption characteristics. However, there is no consistent pattern in the dissolution times reported by Birmingham et al. [1]The rate at which suppositories dissolve does not seem to be a simple function of suppository dose size. Dissolution times decrease within the smaller suppository size group and within the larger size group, yet dissolution times increase from the small to the large suppository size group. The authors admit they have less confidence in this component of their model, and although it may improve the goodness of fit, it is not revealing about any mechanism of suppository dissolution and may have distorted their estimate of Vd/F.

B. J. Anderson, F.A.N.Z.C.A.

Department of Anaesthesia; Auckland Children's Hospital; Park Road; Grafton; Auckland, New Zealand

N. H. G. Holford, F.R.A.C.P.

Associate Professor; Department of Pharmacology and Clinical Pharmacology; Auckland University School of Medicine; Park Road; Grafton; Auckland, New Zealand

(Accepted for publication December 17, 1997.)

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Birmingham PK, Tobin MJ, Henthorn TK, Fisher DM, Berkelhamer MC, Smith FA, Fanta KB, Cote CJ: Twenty-four-hour pharmacokinetics of rectal acetaminophen in children. An old drug with new recommendations. Anesthesiology 1997; 87:244-52.
2.
Anderson BJ, Woolard GA, Holford NHG: Pharmacokinetics of rectal paracetamol after major surgery in children. Paediatr Anaesth 1995; 5:237-42.
3.
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Prescott LF: Paracetamol (acetaminophen), A Critical Bibliographic Review, First Edition. London, Taylor and Francis Publishers, 1996.
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Dange SV, Shah KU, Deshpande AS, Shrotri DS: Bioavailability of acetaminophen after rectal administration. Indian Pediatr 1987; 24:331-2.
Copyright 1998 by the American Society of Anesthesiologists, Inc.