LBOVI-B-4Recombinant human growth hormone (rhGH) has no effect on activities of hepatic cytochrome P4501A2 (CYP1A2), N-acetyltransferase 2 (NAT2), xanthine oxidase (XO) or cytochrome P4502D6 in children with idiopathic growth hormone (GH) deficiency

Abstract

BACKGROUND Growth hormone (GH) is a known modulator of hepatic drug metabolizing enzyme activity. However, previous investigations have used polyfunctional enzyme substrates and the effect on GH on individual hepatic enzyme isoforms remains unknown. This investigation assessed the activities of CYP1A2, NAT-2, XO and CYP2D6 in children receiving GH replacement using the specific probe substrates caffeine and dextromethorphan (DM). METHODS Pre-pubertal children (4–14y, n=12) with idiopathic GH deficiency received DM (0.5mg/kg) and caffeine (11.5mg) prior to and 3 and 6 months following initiation of rhGH therapy. Urine was collected for 8 hours and analyzed via HPLC. Blood was also obtained for CYP2D6 genotyping. The following molar ratios and 95% CI estimation for the mean Δ were calculated: AFMU+1X+1U/17U(CYP1A2), AFMU/AFMU+1X+1U(NAT2), 1U/1U+1X(XO), DM/DX(CYP2D6). Mean baseline ratios were also compared to those obtained at 3 and 6 months using the Student's t-test. RESULTS Mean (95% CI) ratio and Δ values in NAT-2 slow acetylators and CYP2D6 EMs were as follows: (See Table) Ratio Baseline 3 months p Δ 3 months 6 months p Δ 6 months CYP1A2 (n) 5.1 (4.7, 5.6) (11) 5.6 (4.6, 6.6) (11) 0.42 0.47 (−0.33, 1.27) 5.9 (3.9, 7.9) (9) 0.37 0.97 (−0.80, 2.7) NAT2 (n) 0.07 (0.03, 0.11) (11) 0.06 (0.03, 0.10) (11) 0.81 −0.01 (−0.02, 0.01) 0.07 (0.02, 0.12) (9) 0.98 0.07 (0.02, 0.12) XO (n) 0.69 (0.65, 0.73) (11) 0.71 (0.67, 0.75) (11) 0.52 0.02 (−0.02, 0.06) 0.72 (0.66, 0.78) (9) 0.33 0.04 (−0.03, 0.01) CYP2D6 (n) 0.015 (−0.008, 0.037) (10) 0.015 (−0.003, 0.033) (10) 0.97 0.00 (−0.01, 0.01) 0.019 (0.000, 0.039) (8) 0.91 0.002 (−0.03, 0.03) CONCLUSION rhGH does not appear to alter the activities of hepatic CYP1A2, NAT-2, XO or CYP2D6 in children with idiopathic GH deficiency. Altered clearance of drugs in this patient population are likely isoform-specific and thus apparent for selected compounds that are substrates for enzymes other than CYP1A2, NAT-2, XO or CYP2D6. Clinical Pharmacology & Therapeutics (2005) 79, P84–P84; doi: 10.1016/j.clpt.2005.12.300