Ontogeny of Valproic Acid Disposition and Metabolism: A Developmental Study in Postnatal Lambs and Adult Sheep

Harvey Wong; Sanjeev Kumar; Dan W. Rurak; Eddie Kwan; Frank S. Abbott; K. Wayne Riggs

Abstract

The ontogeny of valproic acid (VPA) disposition and metabolism was investigated in developing lambs and adult sheep (Dorset or Suffolk breed). Specifically, we wished to investigate the role of glucuronidation and β-oxidation on VPA elimination during development. Catheters were implanted in a carotid artery, a jugular vein, and the urinary bladder in 10-day-old (10 d;n = 8), 1-month-old (1 M; n = 4), and 2-month-old lambs (2 M; n = 5). In adult sheep (n = 5), catheters were implanted in a femoral artery and vein. After the administration of a 10 mg/kg VPA i.v. bolus, serial blood samples and cumulative urine samples were collected for 36 h in the adult ewes and for 72 h in the lambs. Due to saturable protein binding, age-related differences in VPA clearance were more obvious when examining the total body clearance of unbound drug (Cl^u_tb). Mean Cl^u_tb increased significantly with age up to 2 months (10 d = 2.65 ± 1.16 ml/min/kg; 1 M = 5.11 ± 2.49 ml/min/kg; 2 M = 12.84 ± 3.88 ml/min/kg) before decreasing to adult levels (7.73 ± 2.64 ml/min/kg). Similarly, the urinary recovery of the major metabolite, VPA-glucuronide, was significantly less in 10 d lambs (29.2 ± 16.0% of the dose) when compared with the adult and 2 M groups (both ∼74% of the dose). No differences with age were observed in the portion of the dose excreted as the β-oxidation metabolite, 2-n-propyl-3-oxopentanoic acid. The results suggest that alterations in Cl^u_tb with age may be attributable to postnatal development of enzymes involved in VPA glucuronidation.

Footnotes

Send reprint requests to: Dr. K.W. Riggs, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, B.C., Canada V6T 1Z3. E-mail: riggskw{at}unixg.ubc.ca
↵1 A part of this work was presented at the 1999 Annual Meeting of the American Association of Pharmaceutical Scientists (1999 Nov 14–18, New Orleans, LA) and is abstracted in Pharm Sci Suppl1:S-222.
These studies were supported by funding from the Medical Research Council of Canada. H.W. was the recipient of a Pharmaceutical Manufacturers Association of Canada/Health Research Foundation and Medical Research Council of Canada Graduate Scholarship in Pharmacy. S.K. was the recipient of a University of British Columbia Graduate Fellowship. D.W.R. is the recipient of an investigatorship award from the British Columbia Children's Hospital Foundation.
Abbreviations used are::
VPA
valproic acid
10 d
10-day-old lambs
1 M
1-month-old lambs
2 M
2-month-old lambs
AUC_o-∞
area under the curve of arterial plasma concentration-time profile
AUMC_o-∞
area under the first-moment curve
Cl_r
renal clearance
Cl^u_r
renal clearance for unbound VPA
Cl_tb
total body clearance of the total drug
Cl^u_tb
total body clearance based on unbound drug concentrations
C_max
maximal plasma concentration
f_p
area weighted unbound fraction of the drug
MRT
mean residence time of the total drug
MRT^u
mean residence time of the unbound drug
t_1/2β
terminal elimination half-life of total drug,t^u_1/2β, terminal elimination half-life of unbound drug
t_max
time of occurrence of maximal plasma concentration
Vd_ss
steady-state volume of distribution
Vd_ss′
steady state volume of distribution corrected for the effects of saturable protein binding
Vd^u_ss
steady-state volume of distribution for the unbound drug
(E)-2-ene VPA
2-n-propyl-2-pentenoic acid
3-ene VPA
2-n-propyl-3-pentenoic acid
4-ene VPA
2-n-propyl-4-pentenoic acid
3-keto VPA
2-n-propyl-3-oxopentanoic acid
4-keto VPA
2-n-propyl-4-oxopentanoic acid
3-OH VPA
3-hydroxy VPA
4-OH VPA
4-hydroxy VPA
5-OH VPA
5-hydroxy VPA
2-PSA
2-propylsuccinic acid
2-PGA
2-propylglutaric acid
- Received December 24, 1999.
- Accepted May 2, 2000.